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Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient?
symposium article
Annals of Oncology 23 (Supplement 10): x251–x258, 2012 doi:10.1093/annonc/mds325
Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? B. Tombal* Cliniques universitaires Saint Luc, Université catholique de Louvain, Brussels, Belgium
Prostate cancer (PCa) is the most common malignancy in men. Introduction of prostate-specific antigen (PSA) screening in the early nineties has shifted the diagnosis toward earlier stages. Even in the absence of definitive recommendation on population-based screening, opportunistic PSA-based diagnosis has become the standard of care in industrialized countries. As a result of this, the proportion of patients diagnosed with metastatic PCa has dramatically dropped. In the last update of the European Randomized Study of Screening for PCa, the percentage of men diagnosed with metastatic disease or PSA ≥ 100 ng/ml decreased from 7.9% in the control arm to 2.6% in the PSA-screening arm [1]. This shift in stage has significantly impacted treatment patterns. A vast majority of patients nowadays receive local treatment (i.e. radical prostatectomy, interstitial brachytherapy, or external beam radiotherapy) alone or with adjuvant androgen deprivation therapy (ADT) [2]. In most cases, the entry in systemic disease is declared on an isolated PSA recurrence after local treatment. Even in the absence of robust data, early ADT, by means of gonadotropin-releasing hormone (GnRH) agonist or orchiectomy, has become the standard treatment of isolated biochemical recurrence [3]. Consequently, a large proportion of patients are receiving ADT in the absence of any detectable metastasis. Because ADT is not curative when used alone, a proportion of these patients
*Correspondence to: Dr. B. Tombal, Service d’Urologie, Clinique universitaires Saint Luc, Av. Hippocrates 10, B-1200, Bruxelles, Belgium. E-mail: [email protected]
will progress and become resistant to castration (CRPC). Although CRPC can be defined in case of biochemical, radiological, or clinical progression in a low testosterone environment, most CRPC cases are declared base on an isolated PSA progression in the absence of any detectable metastasis [4]. To some extent, this introduces a bias in our perception of the disease. Indeed, a rise of PSA is a quasipathognomonic signature of the reactivation of the androgen receptor (AR) [5]. However, other pathways of progression exist, not involving reactivation of AR and therefore not associated with PSA progression [5]. The incidence and epidemiology of these progressions are presently unknown. The exact proportion of patient entering CRPC at a nonmetastatic stage (M0) is largely unknown. Kirby et al. have conducted a systematic research on that topic [6]. They have identified only 12 studies including a total of 71 179 patients observed for up to 12 years. Based on that review, they estimated that 10%–20% of patients develop CRPC within ∼5 years of follow-up. Together, ≥84% were shown to have metastases at diagnosis. Of those M0 CRPC patients at diagnosis, 33% could expect to develop bone metastases within 2 years. Subjectively however, it seems that the proportion of M0 CRPC has significantly increased in the last decade, as echoed by the rapid accrual of the large trial program with the bisphosphonate zoledronic acid (ZOL), endothelin receptor A (ETA) inhibitor atrasentan and zybotentan, and the inhibitor of the receptor activator of nuclear factor kappa-B ligand (RANKL), denosumab. The introduction of new imaging techniques may modify that epidemiology in the near future. In M0 CRPC patients, 99m Tc bone scintigraphy (BS) is, in most case, the first exam to
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
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The introduction of early PSA-based diagnosis has profoundly impacted the epidemiology of castration-resistant prostate cancer (CRPC). Many patients enter the disease at an early stage when the only sign of resistance to androgen deprivation therapy (ADT) is a progressive elevation of prostate-specific antigen (PSA). This created a very heterogeneous population of non-metastatic (M0) CRPC. PSA kinetics is the most powerful indicator of aggressiveness in that population and can be used to trigger imaging investigation and enrollment in clinical trials. Several registered and near to come treatments have not been tested in that population but in men with more advanced metastatic and often symptomatic disease. Several agents have been investigated to delay the onset of the first bone metastasis but only one, denosumab, has reached its end-point. Because CRPC remains largely driven by the androgen receptor (AR), physicians have relied on second-line hormonal manipulations to delay the progression of the disease, including first generation antiandrogens, adrenal synthesis inhibitors, steroids and estrogens. The data however are mostly limited to phase II trials. Key words: antiandrogens, castration resistance, prostate cancer, PSA kinetics
symposium article turn positive [7]. The sensitivity of 99mTc BS is limited and the introduction of all-in-one techniques, including positron emission tomography and whole-body magnetic resonance imaging (MRI), is likely to detect metastases at a much lower burden [8]. This once again will impact on the definition of the disease by creating a group of early oligo-metastatic (M+) CRPC.
M0 and early M+ CRPC, the treatment gap
extending the duration of hormone responsiveness using traditional agents As mentioned already, the common physio-pathological for most CRPC is a re-activation of AR transcriptions in a low
x | Tombal
serum testosterone environment that translated biologically by an elevation of the PSA [5]. For many years, physicians have tried to modulate the timing and modalities of hormone therapy to try extending the duration of hormone responsiveness.
GnRH antagonists GnRH agonists (i.e. leuprolide, goserelin, triptorelin, and buserelin) are the standard agents to induce ADT [11]. GnRH agonists are natural peptides mimicking the effect of GnRH by stimulating the receptor, the inhibition of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion being later obtained by desensitization of the receptor. GnRH antagonists (i.e. abarelix and degarelix) are semi-synthetic peptides that block the GnRH receptor and induce immediate and rapid decrease of LH, FSH, and testosterone. A recent sub-analysis of the degarelix registration trial suggests that degarelix delays time-to-PSA castration and thus increases the duration of the response to castration [12]. Using a definition of CRPC more stringent that recommended by the PCa Working Group 2 consensus (i.e. two consecutive increases in PSA of 50% compared with nadir and ≥5 ng/ml on two consecutive measurements at least 2 weeks apart or death), Tombal et al. have showed that patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (P = 0.05) [12, 13]. The probability of completing the study without experiencing PSA recurrence 364 was 91.1% [95% confidence interval (CI) 85.9% to 94.5%] for degarelix and 85.9% (95% CI 79.9% to 90.2%) for leuprolide. These results were confirmed on a longer follow-up and similar data were reported for alkaline phosphatases [14, 15]. However, these data should be considered as preliminary and further confirmations are awaited.
maximal androgen blockade In 1985, Labrie et al. had already postulated that residual production of adrenal androgens could drive PCa growth and recommended to permanently associate an antiandrogen to the GnRH agonist from the initiation of ADT, in a strategy known as maximal androgen blockade (MAB) [16]. Several meta-analyses have shown that MAB provides a statistically significant but limited OS benefit (2%–3%) when compared with GnRH agonist monotherapy [17–19]. The PCa Trialists’ Collaborative Group meta-analysis estimates that MAB increases 5-year survival by 1.8% (P = 0.11) compared with GnRH agonists alone, depending on the class of antiandrogen used. MAB with non-steroidal antiandrogens (NSAAs) nilutamide and flutamide decreases the risk of death over ADT by 8%, which translates into a 2.9% increase in 5-year survival. But NSAAs also increase the rate of side-effects versus MAB alone: diarrhea (10% versus 2%), gastrointestinal pain (7% versus 2%), and non-specific ophthalmologic events (29% versus 5%). Noteworthily, none of the meta-analyses carried out so far have incorporated studies with 50 mg bicalutamide, the most frequently used antiandrogen. Klotz and Schellhammer have indirectly estimated that MAB with bicalutamide could improve survival by 20% over ADT alone,
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Until 2004, CRPC was consistently a rapidly lethal disease. The treatment of CRPC has dramatically changed with the registration of docetaxel and ZOL, which have become the cornerstone day-to-day CRPC’s treatments [9, 10]. Beyond the efficacy of taxanes and bisphosphonates in PCa, these drugs have also moved the treatment of PCa from the urological arena to the multidisciplinary arena. Interestingly however, docetaxel and ZOL were tested in very advanced population. Patients were required to be M+ on baseline 99mTC BS and/or thoraco-abdomino-pelvic computed tomography (CT), which excluded M0 CRPC. In the TAX327 trial with docetaxel, 45% of patients in the mitoxantrone cohort were symptomatic and 22% had visceral disease [10]. In the ZOL registration trial, the mean number (±SD) of bone metastases was 4.2 (±2.6), 78% of patients in the placebo cohort had experienced skeletal-related events, and 73.3% had pain [9]. Subsequently, Food and Drug Administration (FDA) and European Medicine Agency (EMA) registered these drugs for the treatment of M+ CRPC exclusively. TAX327 was initiated in 2000 and the ZOL registration trial in 1998, thus overlapping the current epidemiological change induced by PSA screening. This has created a ‘treatment gap’ of several months between the first rise of PSA under ADT and the occurrence of multiple symptomatic metastases. Once physicians had realized that modern patients were entering CRCP much earlier, endless discussions have emerged on the appropriate time for initiating docetaxel and ZOL. The industry has used and overused that gap, in order to optimize their respective market shares. The management of M0 and early M+ CRPC has therefore become a major challenge for the physicians. Clearly, the endpoints are different. Pain and quality control are important issues in advanced M+ CRPC. Delaying time to progression (TTP), either objectively or by delaying initiation of chemotherapy is clearly an important end-point in M0 and early M+ CRPC, once proven that it does not negatively impact overall survival (OS) and quality of life (QoL). The main problem, however, remains the heterogeneity of that population, as demonstrated by the huge variability in TTP and OS in reported trials. It is therefore critical to understand these determinants of progression to appropriately select patients for further treatments.
Annals of Oncology
symposium article
Annals of Oncology
conferring an additional benefit of 1.5 years to a population of men with a hypothetical survival of 5 years [20].
switching GnRH agonists
antiandrogen withdrawal syndrome Because mutations of the AR frequently occur in a low testosterone environment, antiandrogens may switch to an antagonist activity to an agonist activity and fueled AR activity rather than suppressing it [5]. In patients treated by MAB, interrupting the antiandrogen when the patient becomes CRPC may suppress AR activity and induce PSA response, a
second-line hormonal manipulations In the absence of curative second-line treatment, most physicians have historically prescribed antiandrogens (Table 2), adrenal synthesis inhibitors (Table 3), estrogens and derivatives (Table 4), or steroids (Table 5). Although there is a strong physiological rationale to apply further hormonal
Table 1. Trials evaluating antiandrogen withdrawal (AAW) syndrome Author
Drug
Kelly and Scher [35] Small and Srinivas [36] Herrada et al. [37] Schellhammer et al. [38]
Flutamide Flutamide Flutamide Flutamide Bicalutamide Bicalutamide
Nieh [39]
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
57 82 39 8 14 3
28 15 28 50 29 33
4 3.5 3.3 NR NR 6
% PSA response, % of patients achieving 50% decrease in PSA; NR, not reported.
Table 2. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with antiandrogen Total
Drug
Scher et al. [40] Joyce et al. [41] Kucuk et al. [42] Lodde et al. [43] Fossa et al. [44] Kassouf et al. [45] Desai et al. [46] Debruyne et al. [47]
Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Flutamide (250 mg tid) Nilutamide (200 or 300 mg qd) Nilutamide (150 or 300 mg qd) Cyproterone actetate (100 mg bid)
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
51 31 52 38 101 28 14 161
14 23 20 45 23 29 50 4
4 NR NR 18 4.2 7 11 3.6
% PSA response, % of patients achieving 50% decrease in PSA; AAW, antiandrogen withdrawal; NR, not reported.
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The late reactivation of the AR underlying CRPC may arise from multiple causes. One of these is that GnRH agonists may lose their efficacy over time with the consequence that testosterone increases above the castration level, a phenomenon known as testosterone breakthrough [21]. Morote et al. have investigated the impact of such testosterone breakthroughs on PSA progression-free survival (PFS) in 73 patients receiving GnRH agonists [22]. PSA PFS was, respectively, 88 and 137 months in patients with or without testosterone breakthroughs above 32 ng/dl (P < 0.03). Interestingly, patients treated by MAB with bicalutamide had a similar rate of testosterone breakthroughs but no shortening of PSA PFS. Lawrentschuk et al. have investigated the benefit of re-challenging 39 CRPC patients with a different GNRH agonist. Sixty-nine percent of the patients experience a PSA decrease, the median PSA decrease being 69.3% in patients switching from leuprolide to goserelin and 6.4% in patients switching from goserelin to leuprolide [23].
phenomenon known as antiandrogen withdrawal (AAW) syndrome. A series of reports on AAW is presented in Table 1. Most AAW syndrome are modest PSA response for a few weeks, although dramatic and sustained responses have been reported. The factors predicting the occurrence of AAW have been prospectively studied by the Southwest Oncology Group Trial 9426 on 210 patients previously treated by MAB with flutamide, bicalutamide, or nilutamide [24]. A PSA decrease ≥50% was observed in 21% of patients without any evidence of radiographic response. The median PSA PFS was 3 months. However, 19% of patients experience a PFS interval ≥12 months. The strongest predictors of PSA response are the absence of M+ disease (odds ratio (OR) M+ versus M0 0.42); PSA only progression (OR yes versus non 1.93); and longer duration of MAB. Considering MAB duration of ≤9 months as reference, OR ( p) for PSA response is 1.51 (0.61) for a duration of 10–17 months; 3.87 (0.052) for a duration of 18–32 months; and 5.51 (0.011) for durations >32 months. Practically, it means that an AAW syndrome can be expected in the case of M0 CRPC after a prolonged period of MAB. In contrast, in a patient with a rapid PSA progression or extensive M+ disease despite adding a short course of second-line AA, it is unrealistic to expect PSA response and subsequent therapy should be initiated immediately.
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Table 3. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with adrenal synthesis inhibitors Total
Drug
Small et al. [48] Small et al. [49] Small et al. [50] Harris et al. [51] Millikan et al. [52] Taplin et al. [53] Sartor et al. [54] Kruit et al. [55]
Ketoconazole (400 mg tid) + hydrocortisone Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (200 mg tid) + hydrocortisone Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (400 mg tid) + dutasteride + hydrocortisone Aminoglutethimide (450 mg bid) + AAW + hydrocortisone Aminoglutethimide (1000 mg sid) + AAW + hydrocortisone
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
50 20 128 28 45 57 29 38
63 55 27 46 31 56 48 37
3.5 8.5 8.6 7.5 NR 20 4 9
% PSA response, % of patients achieving 50% decrease in PSA; AAW, antiandrogen withdrawal; NR, not reported.
Total
Drug
Smith et al. [56] Oh et al. [57] Oh et al. [57] Oh et al. [58] Small et al. [59] Pfeifer et al. [60] Osborn et al. [61] Dawson et al. [62] Fossa et al. [63]
DES (1 mg sid) DES (3 mg sid) PC-SPES (3 caps) PC-SPES (6 caps) PC-SPES (9 caps) PC-SPES (9 caps) Megestrol acetate (160–320 mg sid) Megestrol acetate (160versus 640 mg sid) Medroxyprogesterone (1 g. Sid)
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
21 42 43 23 37 16 14 149 21
43 24 40 52 54 81 14 12 30
NA 3.8 NA 2.5 4.0 NR NR NR 2–7
% PSA response, % of patients achieving 50% decrease in PSA; DES, diethylstilbestrol; NR, not reported.
Table 5. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with steroids Total
Drug
Tannock et al. [64] Sartor et al. [44] Fossa et al. [44] Fossa et al. [65] Kelly et al. [66] Kantoff et al. [67] Small et al. [68] Saika et al. [69] Morioka et al. [70] Storlie et al. [71] Venkitaraman et al. [72] Debruyne et al. [47]
Prednisone (7.5–10 mg sid) Prednisone (10 mg bid) Prednisone (5 mg bid) Prednisolone (10 mg bid) Hydrocortisone (40 mg qd) Hydrocortisone (30/10 mg qd) Hydrocortisone (40 mg qd) Dexamethasone (1.5 mg sid) Dexamethasone (1.5 mg sid) Dexamethasone (0.75 mg bid) Dexamethasone (0.5 mg qd) Lyarozole (300 mg bid)
Patients (n)
Prostate-specific antigen (PSA) response
Duration (months)
81 29 101 50 30 78 230 19 27 38 102 160
22 34 21 26 20 14 16 28 59 61 49 20
4 2.0 4.2 4 4 2.3 2.3 NR NR NR 7.4 NR
% PSA response, % of patients achieving 50% decrease in PSA; NA, not available.
manipulation, the clinical data are scarce. Tables 2–5 report exclusively the results of the phase II trial reporting modest PSA decrease for short duration. There is no reported phase III trial. Objective responses are seldom reported and, so far, with the exceptions of novel agents abiraterone and MDV3100, there has never been published reports of OS benefit. Noteworthily, the benefit of adding an antiandrogen to a GnRH agonist seems primarily linked to the ability of that GnRH agonist to effectively suppress testosterone and to the
x | Tombal
importance of androgens secretion by the adrenals. Hashimoto et al. have investigated whether serum testosterone predicted the efficacy of second-line bicalutamide or flutamide [25]. PSA response ≥50% was observed in 77.3% and 37.5% of patients with a testosterone ≥ or <5 ng/dl (P = 0.04), respectively. In addition, a testosterone <5 ng/dl was an independent factor to predict PSA PFS; 1-year PSA PFS was 52.9% versus 0% in patients with a testosterone ≥ or <5 ng/dl (P 0.002), respectively. Narimoto et al. have examined the effects of
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Table 4. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with estrogen and derivatives
Annals of Oncology
flutamide as a second-line antiandrogen in 16 CRPC patients initially treated with bicalutamide [26]. A PSA decline ≥50% was observed in 50% of the patients with a median response of 6.25 months. An elevated baseline androstenediol level was a predictive factor of PSA response and a low DHEA group a predictor of a prolonged response.
epidemiology and kinetics of metastatic progression in M0 CRCP
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941 M0 CRPC with ETA atrasentan [7]. More stringent PSA kinetic parameters were requested. The PSA levels had to be at least 20 ng/ml within 12 months, or had increased by 50% within 6 months (minimum, 1 ng/ml at screening), or had been rising (two sequential increases with a confirmatory third increase) within 12 months (minimum, 1 ng/ml at screening). As a result of this selection, the mean (±SD) PSA DT was 5.9 (±3.62) months versus 9.7 (±4.7) months in the ZOL trials [7, 27]. Smith et al. have reported the data of the 331 men in the placebo group [28]. At 2 years, 46% of subjects had developed bone metastases, and 20% had died. The median BM-PFS was 25 months. In multivariate analyses, baseline PSA < 13.1 ng/ml was associated with shorter OS (RR 2.34; 95% CI 1.71–3.21; P < 0.0001), time to first bone metastasis (RR 1.98; 95% CI 1.43–2.74; P < 0.0001), and BM-PFS (RR 1.98; 95% CI 1.45–2.70; P < 0.0001). PSA velocity was significantly associated with OS and BM-PFS. Other covariates were not consistently associated with clinical outcomes. In contrast to the ZOL trial, patients were followed by 99mTC BS and CT or MRI, which allow testing the distribution of metastatic sites. Looking at the placebo cohort, progression was reported in 56.3% of the patients. Extra-skeletal lesions were cited as the primary metastatic manifestation of disease progression in only 8% of the patients, while skeletal lesions were cited as the primary metastatic progression in 44.3% of the patients. This confirmed that in approximately one patient out of five, the first metastatic site is the skeleton. The third trial was conducted by Smith et al. and has investigated the benefit of denosumab, in 1432 M0 CRCP patients [29]. The inclusion criteria specifically required a baseline PSA ≥ 8.0 ng/ml or a PSA DT ≤10.0 months, or both. Patients were followed by 99mTC BS, extraskeletal progression being only recorded by investigators. The median BM-PFS survival was 25.2 months in the placebo arm. Further sub-analyses have been reported with the aim of identifying subsets of higher-risk M0 CRPC patients who would benefit from the treatment [30]. The median BM-PFS are 22.4 months in patients with a PSA DT ≤ 10 months, 18.7 months in patients with a PSA DT ≤ 6 months, and 18.3 months in patients with a PSA DT ≤ 4 months. These studies pinpoint at three important messages. The first one is a confirmation that the skeleton is by far the first metastatic site in advanced CRPC. This provides a strong rationale for developing newer and better imaging modalities to assess the extent and progression of bone metastasis and to test earlier use of bone-targeted agents. Second, they suggest that the M0 CRCP is a heterogeneous population that overall progresses slowly, with median BMF PFS longer than 2 years. Considering the potential toxic effect of most of the available agents, this sounds as a plea to recommend active surveillance of these patients and not rely on their anxiety to anticipate, without strong rational, prescription of agents registered in metastatic patients. Finally, they confirm that PSA kinetics, and especially PSA DT, is the most useful parameter in the day-today life to counsel the patients and schedule the imaging tests.
the ‘Holy Grail’ of metastasis prevention M0 CRPC is a health state where most patients are usually strictly asymptomatic, but for the side-effects of ADT. In the
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The exact proportion of patients having CRPC before developing metastases is presently unknown. One of the explanations is the lack of clear recommendation regarding frequency and modality of imaging. Because physicians follow these patients with PSA, M0 CRPC occurs almost consistently first. Very few good quality surveys exist on the topic. Three prospective trials have investigated the potential benefit of bone-targeted agents ZOL, atrasentan, and denosumab on the development of metastases and especially bone metastases in M0 CRPC patients. Beyond the results, these data have provided a good epidemiological background to better characterize the risk of progression in that heterogeneous population. Smith et al. have conducted a randomized, doubleblind, placebo-controlled trial to evaluate the effects of ZOL on time to first bone metastasis in men with M0 CRPC defined by a rising PSA despite ADT [27]. The study was terminated before completion of accrual after an interim analysis demonstrated that the observed event rate was lower than expected. CT were not carried out, only 99mTC BS, so that this study provides information only on the rate and risk factor of bone metastases in the 201 patients from the placebo group [27]. The first observation was that the median bone metastasis PFS (BM-PFS) time was 30 months, much longer than expected. At 2 years, only 33% of patients had developed bone metastases and median time to first bone metastases and median OS were not reached. The inclusion criteria did not restrict entry in the trial to patients with a minimum PSA doubling time (DT). PSA progression was simply defined as three consecutive rises in serum PSA measured at least 2 weeks apart with an initial PSA rise within 10 months of study entry, and a last PSA ≥ 150% blood cell count nadir value. Patients with an intact prostate had a PSA level <4 ng/ml and those with radical prostatectomy had a PSA level <0.8 ng/ml. This study has helped us to understand the determinant of progression to bone metastases. The baseline PSA level <10 ng/ml [relative risk (RR) 3.18; 95% CI 1.74–5.80; P < 0.001] and PSA velocity (RR 4.34 for each 0.01 increase in PSA velocity; 95% CI 2.30–8.21; P < 0.001) independently predicted shorter time to first bone metastasis and OS. Tertiles of PSA (<7.7, 7.7 to 24, >24 ng/ml) and PSA DT (<6.3, 6.3 to 18.8, >18.8 months) were associated with different BM-PFS (P < 0.001). Other standard parameters of PCa aggressiveness did not predict the time to first bone metastases, including prior prostatectomy, Gleason sum >7, regional lymph node metastases at diagnosis, time from ADT to randomization >2 years, and time from diagnosis to randomization. With that information available, Nelson et al. have conducted a similar double blind, placebo-controlled trial in
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Annals of Oncology
Table 6. Summary of bone metastasis prevention trial in M0 PCa patients treated with androgen deprivation therapy (ADT) Study
Patients
Treatment arms
Selected end-points
MRC PR04 [31, 73]
T2−4
Clodronate versus placebo
Zometa 703 [27]3
Castration-resistant prostate cancer (CRPC) T2a (Gleason ≥ 7,PSA ≥ 10 ng/ml); or T2b−4, N0 High-risk patients starting ADT
ZOL versus placebo
Time to symptomatic BM or Primary not met PCa death, OS Time to first BM, OS, BM-PFS Terminated early
EBRT + ADT ± ZOL
PSA PFS, OS, BM-PFS
Ongoing
OS, QoL, SREs, PFS
Ongoing
BM rate, OS, PSA DT BM-PFS, PSA PFS, OS, BMPFS, PSA DT PFS, OS
Ongoing Primary not met
RADAR [74]4 STAMPEDE [75]5 ZEUS [76]6 M00–244 [7]
ZOL versus docetaxel versus celecoxib, Gleason 8−10; pN+ or PSA ≥ 20 ng/ml ZOL versus standard treatment CRPC Atrasentan versus placebo
Enthuse M0 [34]8
CRPC
Zibotentan versus placebo
Results/status
Terminated early
denosumab prevention trial, serious adverse events in the placebo arm were rare [29]. Therefore, it has become as a major challenge to delay as long as possible this health state by delaying the onset of the first bone metastasis. Several trials have taken that challenge (Table 6). In addition to the aforementioned trial with ZOL, Mason et al. have conducted a randomized double-blind placebo-controlled trial to test the efficacy of oral bisphosphonate clodronate in 508 nonmetastatic PCa patients at high risk of developing bone metastases [31]. These patients were not M0 CRPC strictly speaking but patients receiving clodronate as adjuvant to ADT (stage T2–T4, N0, N+ or NX, M0). After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of BM-PFS. Three other trials are ongoing, all testing adjuvant ZOL in high-risk M0 patients receiving ADT. ETA inhibitors have been identified in the mid nineties as key mediators of bone metastases in PCa. Two agents have been tested, atrasentan and zibotentan, both suggesting promising results in phase II trials, generating a worldwide enthusiasm [32, 33]. Two large phases III have been initiated in the M0 CRPC setting with the ambitious end-points of prolonging time to first bone metastasis but also OS. The primary was not met for the atrasentan trial and the independent data monitoring committee prematurely closed the zibotentan trial [7, 34]. Smith et al. have recently reported the results of a randomized, placebo-controlled trial testing denosumab in 1432 M0 CRPC patients. In that patient population with a PSA ≥ 8 ng/ml and/or a PSA DT ≤ 10 months, denosumab significantly increased BM-PFS by a median of 4.2 months compared with placebo. The median BM-PFS was 29.5 (95% CI 25.4–33.3) months in patients receiving denosumab versus 25.2 (95% CI 22.2–29.5) in patients receiving placebo; the hazard ratio (HR) for BM-PFS is 0.85 (95% CI 0.73–0.98, P = 0.028). OS did not differ between patients receiving early denosumab and placebo. The rates of adverse events and serious adverse events were similar in both the groups, except for osteonecrosis of the jaw (5% in denosumab versus 0% in
x | Tombal
placebo) and hypocalcemia (2% in denosumab versus <1% on placebo). Although that trial is the first to demonstrate that interfering with the physiology of the bone microenvironment can delay bone metastasis in men with PCa, it is under extensive discussion. On one hand, we must acknowledge that this is a major proof-of-concept on the role of RANK-L in the development of bone metastases. Clinically speaking however, we must still understand the relevance and impact of delaying metastases by 4 months on the natural history of the disease. The major limitation indeed is that no recommendation was made on pursuing denosumab after bone metastases progression. As a result, data are not available on the impact on delaying SRE or symptoms. In the absence of even a trend on OS, our reading of the clinical impact is clearly limited. Attempts have been made to identify a subset of patients in which denosumab would confer a higher benefit on BMF survival [30]. As mentioned earlier, BM-PFS decreases with lower PSA DT cut-offs. Interestingly, the benefit of denosumab increases in these subsets of patients. Denosumab increases BM-PFS survival by 6.0 months in patients with a PSA DT ≤ 10 months (HR = 0.85; P = 0.028), by 7.2 months in patients with a PSA DT ≤ 6 months (HR = 0.77; P = 0.006), and by 7.5 months in patients with a PSA DT ≤ 4 months (HR = 0.71; P = 0.004). Of note, these subsets of patients represent 81%, 59.1%, and 39% of the study population, respectively.
conclusion The introduction of early PSA-based diagnosis has impacted the epidemiology of CRPC. Many patients nowadays enter the disease at an early stage when the only sign of resistance to ADT is a progressive elevation of PSA. Physicians confronted to these patients should recognize three important facts. First, although the disease remains largely driven by the AR, the benefit of second-line hormonal manipulations, including first generation antiandrogens, adrenal synthesis inhibitors, steroids and estrogens, is clearly limited. There are no data indicating a clear benefit beyond PSA response. Now that several drugs are available to effectively treat CRPC, the rationale for prescribing
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BM, bone metastasis; BM-PFS, bone metastasis progression-free survival; EBRT, external beam radiotherapy; PFS, progression-free survival; ZOL, zoledronic acid; DT, doubling time; OS, overall survival; QoL, quality of life; SRE, skeletal-related event; PSA, prostate-specific antigen. STAMPEDE includes M0 and M+ patients.
Annals of Oncology
these drugs should be revisited. Second, physicians following CRPC should recognize that M0 CRPC is an extremely heterogeneous stage of the disease, with most patients progressing slowly to a metastatic stage. Currently, the kinetics of PSA progression appear to be the best indicator of progression and the optimal tool to identify high-risk patients. Finally, and most importantly, physicians should acknowledge that the available registered treatments have been studied in far more advanced stage of the disease. There is absolutely no evidence that the efficacy/toxic effect profile is preserved if these drugs are prescribed at a much earlier stage of the disease. This will have to be kept in mind, especially in face of the development of more sensitive imaging techniques.
disclosure
references 1. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366(11): 981–990. 2. Cooperberg MR, Broering JM, Kantoff PW, Carroll PR. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol 2007; 178(3 Pt 2): S14–S19. 3. de la Taille A. Circumstances of prescription of hormone therapy for patients with prostate cancer. Progres en urologie: journal de l’Association francaise d’urologie et de la Societe francaise d’urologie 2009; 19(5): 313–320. 4. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26(7): 1148–1159. 5. Tombal B. What is the pathophysiology of a hormone-resistant prostate tumour? Eur J Cancer 2011; 47(Suppl. 3): S179–S188. 6. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract 2011; 65(11): 1180–1192. 7. Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 2008; 113(9): 2478–2487. 8. Tombal B, Lecouvet F. Modern detection of prostate cancer’s bone metastasis: is the bone scan era over? Adv Urol 2012; 2012: 893193. 9. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96(11): 879–882. 10. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502–1512. 11. Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L et al. Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev 2005; 26(3): 361–379. 12. Tombal B, Miller K, Boccon-Gibod L, Schroder F, Shore N, Crawford ED et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010; 57(5): 836–842. 13. Scher HI, Morris MJ, Basch E, Heller G. End points and outcomes in castrationresistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol 2011; 29(27): 3695–3704. 14. Crawford D, Moul J, Shore N, Olesen T, Persson B. Switching from leuprolide to degarelix vs continuous degarelix treatment––effects on long-term prostatespecific antigen control. J Urol 2010; 183(4): e262.
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15. Schroder FH, Tombal B, Miller K, Boccon-Gibod L, Shore ND, Crawford ED et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106(2): 182–187. 16. Labrie F, Dupont A, Belanger A. Complete androgen blockade for the treatment of prostate cancer. Important Adv Oncol 1985: 193–217. 17. Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002; 95(2): 361–376. 18. Schmitt B, Bennett C, Seidenfeld J, Samson D, Wilt TJ. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 1999(2): CD001526. 19. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000; 355(9214): 1491–1498. 20. Klotz L, Schellhammer P. Combined androgen blockade: the case for bicalutamide. Clin Prostate Cancer 2005; 3(4): 215–219. 21. Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy. Eur Urol Suppl 2008; 7(1): 15–21. 22. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 2007; 178(4 Pt 1): 1290–1295. 23. Lawrentschuk N, Fernandes K, Bell D, Barkin J, Fleshner N. Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. J Urol 2011; 185(3): 848–854. 24. Sartor AO, Tangen CM, Hussain MH, Eisenberger MA, Parab M, Fontana JA et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer 2008; 112(11): 2393–2400. 25. Hashimoto K, Masumori N, Hashimoto J, Takayanagi A, Fukuta F, Tsukamoto T. Serum testosterone level to predict the efficacy of sequential use of antiandrogens as second-line treatment following androgen deprivation monotherapy in patients with castration-resistant prostate cancer. Jpn J Clin Oncol 2011; 41(3): 405–410. 26. Narimoto K, Mizokami A, Izumi K, Mihara S, Sawada K, Sugata T et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a secondline anti-androgen. Int J Urol 2010; 17(4): 337–345. 27. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 23(13): 2918–2925. 28. Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer 2011: 117(10): 2077–2085. 29. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379(9810): 39–46. 30. Smith M, Saad F, Shore N, Oudard S, Miller K, Tombal B et al. Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics. J Clin Oncol 2012; 30(suppl 5) (Abstr 6). 31. Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, Sokal M et al. Oral sodium clodronate for nonmetastatic prostate cancer–results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007; 99(10): 765–776. 32. Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003; 21(4): 679–689. 33. James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol 2009; 55(5): 1112–1123.
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BT is an investigator or a consultant for Astellas, Amgen, Ferring, Medivation, Janssens, Sanofi-Aventis.
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55. Kruit WH, Stoter G, Klijn JG. Effect of combination therapy with aminoglutethimide and hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to standard endocrine therapy. Anti-cancer drugs 2004; 15(9): 843–847. 56. Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ. A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 1998; 52(2): 257–260. 57. Oh WK, Kantoff PW, Weinberg V, Jones G, Rini BI, Derynck MK et al. Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004; 22(18): 3705–3712. 58. Oh WK, George DJ, Hackmann K, Manola J, Kantoff PW. Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 2001; 57(1): 122–126. 59. Small EJ, Frohlich MW, Bok R, Shinohara K, Grossfeld G, Rozenblat Z et al. Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 2000; 18(21): 3595–3603. 60. Pfeifer BL, Pirani JF, Hamann SR, Klippel KF. PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 2000; 85(4): 481–485. 61. Osborn JL, Smith DC, Trump DL. Megestrol acetate in the treatment of hormone refractory prostate cancer. Am J Clin Oncol 1997; 20(3): 308–310. 62. Dawson NA, Conaway M, Halabi S, Winer EP, Small EJ, Lake D et al. A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma: cancer and leukemia group B study 9181. Cancer 2000; 88(4): 825–834. 63. Fossa SD, Jahnsen JU, Karlsen S, Ogreid P, Haveland H, Trovag A. High-dose medroxyprogesterone acetate versus prednisolone in hormone-resistant prostatic cancer. A pilot study. Eur Urol 1985; 11(1): 11–16. 64. Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989; 7(5): 590–597. 65. Fossa SD, Jacobsen AB, Ginman C, Jacobsen IN, Overn S, Iversen JR et al. Weekly docetaxel and prednisolone versus prednisolone alone in androgen-independent prostate cancer: a randomized phase II study. Eur Urol 2007; 52(6): 1691–1698. 66. Kelly WK, Curley T, Leibretz C, Dnistrian A, Schwartz M, Scher HI. Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer. J Clin Oncol 1995; 13(9): 2208–2213. 67. Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17(8): 2506–2513. 68. Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 2000; 18(7): 1440–1450. 69. Saika T, Kusaka N, Tsushima T, Yamato T, Ohashi T, Suyama B et al. Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients. Int J Urol 2001; 8(6): 290–294. 70. Morioka M, Kobayashi T, Furukawa Y, Jo Y, Shinkai M, Matsuki T et al. Prostatespecific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexamethasone. Urol Int 2002; 68(1): 10–15. 71. Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 1995; 76(1): 96–100. 72. Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC. Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU Int 2008; 101(4): 440–443. 73. Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 2009; 10(9): 872–876. 74. http://www.clinicaltrials.gov/ct2/show/NCT00193856?term=radar+zoledronic&rank=1. 75. http://www.clinicaltrials.gov/ct2/show/NCT00268476?term=stampede&rank=1. 76. http://www.controlled-trials.com/ISRCTN66626762/zeus.
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34. http://www.astrazeneca.com/Media/Press-releases/Article/0022011AstraZenecahalts-phase-III-trial-of-ZIBOTENTAN. 35. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol 1993; 149(3): 607–609. 36. Small EJ, Srinivas S. The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer 1995; 76(8): 1428–1434. 37. Herrada J, Dieringer P, Logothetis CJ. Characterization of patients with androgenindependent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal. J Urol 1996; 155(2): 620–623. 38. Schellhammer PF, Venner P, Haas GP, Small EJ, Nieh PT, Seabaugh DR et al. Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade. J Urol 1997; 157(5): 1731–1735. 39. Nieh PT. Withdrawal phenomenon with the antiandrogen casodex. J Urol 1995; 153(3 Pt 2): 1070–1072; discussion 1072–3. 40. Scher HI, Liebertz C, Kelly WK, Mazumdar M, Brett C, Schwartz L et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15(8): 2928–2938. 41. Joyce R, Fenton MA, Rode P, Constantine M, Gaynes L, Kolvenbag G et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159(1): 149–153. 42. Kucuk O, Fisher E, Moinpour CM, Coleman D, Hussain MH, Sartor AO et al. Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a southwest oncology group study (SWOG 9235). Urology 2001; 58(1): 53–58. 43. Lodde M, Lacombe L, Fradet Y. Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer. Urology 2010; 76(5): 1189–1193. 44. Fossa SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001; 19(1): 62–71. 45. Kassouf W, Tanguay S, Aprikian AG. Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails. J Urol 2003; 169(5): 1742–1744. 46. Desai A, Stadler WM, Vogelzang NJ. Nilutamide: possible utility as a second-line hormonal agent. Urology 2001; 58(6): 1016–1020. 47. Debruyne FJ, Murray R, Fradet Y, Johansson JE, Tyrrell C, Boccardo F et al. Liarozole–a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group. Urology 1998; 52(1): 72–81. 48. Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997; 157(4): 1204–1207. 49. Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer 1997; 80(9): 1755–1759. 50. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004; 22 (6): 1025–1033. 51. Harris KA, Weinberg V, Bok RA, Kakefuda M, Small EJ. Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol 2002; 168(2): 542–545. 52. Millikan R, Baez L, Banerjee T, Wade J, Edwards K, Winn R et al. Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol Oncol 2001; 6(3): 111–115. 53. Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L et al. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res 2009; 15(22): 7099–7105. 54. Sartor O, Cooper M, Weinberger M, Headlee D, Thibault A, Tompkins A et al. Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of ‘hormone-refractory’ prostate cancer. J Natl Cancer Ins 1994; 86(3): 222–227.
Annals of Oncology
Annals of Oncology 23 (Supplement 10): x251–x258, 2012 doi:10.1093/annonc/mds325
Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? B. Tombal* Cliniques universitaires Saint Luc, Université catholique de Louvain, Brussels, Belgium
Prostate cancer (PCa) is the most common malignancy in men. Introduction of prostate-specific antigen (PSA) screening in the early nineties has shifted the diagnosis toward earlier stages. Even in the absence of definitive recommendation on population-based screening, opportunistic PSA-based diagnosis has become the standard of care in industrialized countries. As a result of this, the proportion of patients diagnosed with metastatic PCa has dramatically dropped. In the last update of the European Randomized Study of Screening for PCa, the percentage of men diagnosed with metastatic disease or PSA ≥ 100 ng/ml decreased from 7.9% in the control arm to 2.6% in the PSA-screening arm [1]. This shift in stage has significantly impacted treatment patterns. A vast majority of patients nowadays receive local treatment (i.e. radical prostatectomy, interstitial brachytherapy, or external beam radiotherapy) alone or with adjuvant androgen deprivation therapy (ADT) [2]. In most cases, the entry in systemic disease is declared on an isolated PSA recurrence after local treatment. Even in the absence of robust data, early ADT, by means of gonadotropin-releasing hormone (GnRH) agonist or orchiectomy, has become the standard treatment of isolated biochemical recurrence [3]. Consequently, a large proportion of patients are receiving ADT in the absence of any detectable metastasis. Because ADT is not curative when used alone, a proportion of these patients
*Correspondence to: Dr. B. Tombal, Service d’Urologie, Clinique universitaires Saint Luc, Av. Hippocrates 10, B-1200, Bruxelles, Belgium. E-mail: [email protected]
will progress and become resistant to castration (CRPC). Although CRPC can be defined in case of biochemical, radiological, or clinical progression in a low testosterone environment, most CRPC cases are declared base on an isolated PSA progression in the absence of any detectable metastasis [4]. To some extent, this introduces a bias in our perception of the disease. Indeed, a rise of PSA is a quasipathognomonic signature of the reactivation of the androgen receptor (AR) [5]. However, other pathways of progression exist, not involving reactivation of AR and therefore not associated with PSA progression [5]. The incidence and epidemiology of these progressions are presently unknown. The exact proportion of patient entering CRPC at a nonmetastatic stage (M0) is largely unknown. Kirby et al. have conducted a systematic research on that topic [6]. They have identified only 12 studies including a total of 71 179 patients observed for up to 12 years. Based on that review, they estimated that 10%–20% of patients develop CRPC within ∼5 years of follow-up. Together, ≥84% were shown to have metastases at diagnosis. Of those M0 CRPC patients at diagnosis, 33% could expect to develop bone metastases within 2 years. Subjectively however, it seems that the proportion of M0 CRPC has significantly increased in the last decade, as echoed by the rapid accrual of the large trial program with the bisphosphonate zoledronic acid (ZOL), endothelin receptor A (ETA) inhibitor atrasentan and zybotentan, and the inhibitor of the receptor activator of nuclear factor kappa-B ligand (RANKL), denosumab. The introduction of new imaging techniques may modify that epidemiology in the near future. In M0 CRPC patients, 99m Tc bone scintigraphy (BS) is, in most case, the first exam to
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
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The introduction of early PSA-based diagnosis has profoundly impacted the epidemiology of castration-resistant prostate cancer (CRPC). Many patients enter the disease at an early stage when the only sign of resistance to androgen deprivation therapy (ADT) is a progressive elevation of prostate-specific antigen (PSA). This created a very heterogeneous population of non-metastatic (M0) CRPC. PSA kinetics is the most powerful indicator of aggressiveness in that population and can be used to trigger imaging investigation and enrollment in clinical trials. Several registered and near to come treatments have not been tested in that population but in men with more advanced metastatic and often symptomatic disease. Several agents have been investigated to delay the onset of the first bone metastasis but only one, denosumab, has reached its end-point. Because CRPC remains largely driven by the androgen receptor (AR), physicians have relied on second-line hormonal manipulations to delay the progression of the disease, including first generation antiandrogens, adrenal synthesis inhibitors, steroids and estrogens. The data however are mostly limited to phase II trials. Key words: antiandrogens, castration resistance, prostate cancer, PSA kinetics
symposium article turn positive [7]. The sensitivity of 99mTc BS is limited and the introduction of all-in-one techniques, including positron emission tomography and whole-body magnetic resonance imaging (MRI), is likely to detect metastases at a much lower burden [8]. This once again will impact on the definition of the disease by creating a group of early oligo-metastatic (M+) CRPC.
M0 and early M+ CRPC, the treatment gap
extending the duration of hormone responsiveness using traditional agents As mentioned already, the common physio-pathological for most CRPC is a re-activation of AR transcriptions in a low
x | Tombal
serum testosterone environment that translated biologically by an elevation of the PSA [5]. For many years, physicians have tried to modulate the timing and modalities of hormone therapy to try extending the duration of hormone responsiveness.
GnRH antagonists GnRH agonists (i.e. leuprolide, goserelin, triptorelin, and buserelin) are the standard agents to induce ADT [11]. GnRH agonists are natural peptides mimicking the effect of GnRH by stimulating the receptor, the inhibition of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion being later obtained by desensitization of the receptor. GnRH antagonists (i.e. abarelix and degarelix) are semi-synthetic peptides that block the GnRH receptor and induce immediate and rapid decrease of LH, FSH, and testosterone. A recent sub-analysis of the degarelix registration trial suggests that degarelix delays time-to-PSA castration and thus increases the duration of the response to castration [12]. Using a definition of CRPC more stringent that recommended by the PCa Working Group 2 consensus (i.e. two consecutive increases in PSA of 50% compared with nadir and ≥5 ng/ml on two consecutive measurements at least 2 weeks apart or death), Tombal et al. have showed that patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (P = 0.05) [12, 13]. The probability of completing the study without experiencing PSA recurrence 364 was 91.1% [95% confidence interval (CI) 85.9% to 94.5%] for degarelix and 85.9% (95% CI 79.9% to 90.2%) for leuprolide. These results were confirmed on a longer follow-up and similar data were reported for alkaline phosphatases [14, 15]. However, these data should be considered as preliminary and further confirmations are awaited.
maximal androgen blockade In 1985, Labrie et al. had already postulated that residual production of adrenal androgens could drive PCa growth and recommended to permanently associate an antiandrogen to the GnRH agonist from the initiation of ADT, in a strategy known as maximal androgen blockade (MAB) [16]. Several meta-analyses have shown that MAB provides a statistically significant but limited OS benefit (2%–3%) when compared with GnRH agonist monotherapy [17–19]. The PCa Trialists’ Collaborative Group meta-analysis estimates that MAB increases 5-year survival by 1.8% (P = 0.11) compared with GnRH agonists alone, depending on the class of antiandrogen used. MAB with non-steroidal antiandrogens (NSAAs) nilutamide and flutamide decreases the risk of death over ADT by 8%, which translates into a 2.9% increase in 5-year survival. But NSAAs also increase the rate of side-effects versus MAB alone: diarrhea (10% versus 2%), gastrointestinal pain (7% versus 2%), and non-specific ophthalmologic events (29% versus 5%). Noteworthily, none of the meta-analyses carried out so far have incorporated studies with 50 mg bicalutamide, the most frequently used antiandrogen. Klotz and Schellhammer have indirectly estimated that MAB with bicalutamide could improve survival by 20% over ADT alone,
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Until 2004, CRPC was consistently a rapidly lethal disease. The treatment of CRPC has dramatically changed with the registration of docetaxel and ZOL, which have become the cornerstone day-to-day CRPC’s treatments [9, 10]. Beyond the efficacy of taxanes and bisphosphonates in PCa, these drugs have also moved the treatment of PCa from the urological arena to the multidisciplinary arena. Interestingly however, docetaxel and ZOL were tested in very advanced population. Patients were required to be M+ on baseline 99mTC BS and/or thoraco-abdomino-pelvic computed tomography (CT), which excluded M0 CRPC. In the TAX327 trial with docetaxel, 45% of patients in the mitoxantrone cohort were symptomatic and 22% had visceral disease [10]. In the ZOL registration trial, the mean number (±SD) of bone metastases was 4.2 (±2.6), 78% of patients in the placebo cohort had experienced skeletal-related events, and 73.3% had pain [9]. Subsequently, Food and Drug Administration (FDA) and European Medicine Agency (EMA) registered these drugs for the treatment of M+ CRPC exclusively. TAX327 was initiated in 2000 and the ZOL registration trial in 1998, thus overlapping the current epidemiological change induced by PSA screening. This has created a ‘treatment gap’ of several months between the first rise of PSA under ADT and the occurrence of multiple symptomatic metastases. Once physicians had realized that modern patients were entering CRCP much earlier, endless discussions have emerged on the appropriate time for initiating docetaxel and ZOL. The industry has used and overused that gap, in order to optimize their respective market shares. The management of M0 and early M+ CRPC has therefore become a major challenge for the physicians. Clearly, the endpoints are different. Pain and quality control are important issues in advanced M+ CRPC. Delaying time to progression (TTP), either objectively or by delaying initiation of chemotherapy is clearly an important end-point in M0 and early M+ CRPC, once proven that it does not negatively impact overall survival (OS) and quality of life (QoL). The main problem, however, remains the heterogeneity of that population, as demonstrated by the huge variability in TTP and OS in reported trials. It is therefore critical to understand these determinants of progression to appropriately select patients for further treatments.
Annals of Oncology
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Annals of Oncology
conferring an additional benefit of 1.5 years to a population of men with a hypothetical survival of 5 years [20].
switching GnRH agonists
antiandrogen withdrawal syndrome Because mutations of the AR frequently occur in a low testosterone environment, antiandrogens may switch to an antagonist activity to an agonist activity and fueled AR activity rather than suppressing it [5]. In patients treated by MAB, interrupting the antiandrogen when the patient becomes CRPC may suppress AR activity and induce PSA response, a
second-line hormonal manipulations In the absence of curative second-line treatment, most physicians have historically prescribed antiandrogens (Table 2), adrenal synthesis inhibitors (Table 3), estrogens and derivatives (Table 4), or steroids (Table 5). Although there is a strong physiological rationale to apply further hormonal
Table 1. Trials evaluating antiandrogen withdrawal (AAW) syndrome Author
Drug
Kelly and Scher [35] Small and Srinivas [36] Herrada et al. [37] Schellhammer et al. [38]
Flutamide Flutamide Flutamide Flutamide Bicalutamide Bicalutamide
Nieh [39]
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
57 82 39 8 14 3
28 15 28 50 29 33
4 3.5 3.3 NR NR 6
% PSA response, % of patients achieving 50% decrease in PSA; NR, not reported.
Table 2. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with antiandrogen Total
Drug
Scher et al. [40] Joyce et al. [41] Kucuk et al. [42] Lodde et al. [43] Fossa et al. [44] Kassouf et al. [45] Desai et al. [46] Debruyne et al. [47]
Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Bicalutamide (150 mg qd) Flutamide (250 mg tid) Nilutamide (200 or 300 mg qd) Nilutamide (150 or 300 mg qd) Cyproterone actetate (100 mg bid)
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
51 31 52 38 101 28 14 161
14 23 20 45 23 29 50 4
4 NR NR 18 4.2 7 11 3.6
% PSA response, % of patients achieving 50% decrease in PSA; AAW, antiandrogen withdrawal; NR, not reported.
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The late reactivation of the AR underlying CRPC may arise from multiple causes. One of these is that GnRH agonists may lose their efficacy over time with the consequence that testosterone increases above the castration level, a phenomenon known as testosterone breakthrough [21]. Morote et al. have investigated the impact of such testosterone breakthroughs on PSA progression-free survival (PFS) in 73 patients receiving GnRH agonists [22]. PSA PFS was, respectively, 88 and 137 months in patients with or without testosterone breakthroughs above 32 ng/dl (P < 0.03). Interestingly, patients treated by MAB with bicalutamide had a similar rate of testosterone breakthroughs but no shortening of PSA PFS. Lawrentschuk et al. have investigated the benefit of re-challenging 39 CRPC patients with a different GNRH agonist. Sixty-nine percent of the patients experience a PSA decrease, the median PSA decrease being 69.3% in patients switching from leuprolide to goserelin and 6.4% in patients switching from goserelin to leuprolide [23].
phenomenon known as antiandrogen withdrawal (AAW) syndrome. A series of reports on AAW is presented in Table 1. Most AAW syndrome are modest PSA response for a few weeks, although dramatic and sustained responses have been reported. The factors predicting the occurrence of AAW have been prospectively studied by the Southwest Oncology Group Trial 9426 on 210 patients previously treated by MAB with flutamide, bicalutamide, or nilutamide [24]. A PSA decrease ≥50% was observed in 21% of patients without any evidence of radiographic response. The median PSA PFS was 3 months. However, 19% of patients experience a PFS interval ≥12 months. The strongest predictors of PSA response are the absence of M+ disease (odds ratio (OR) M+ versus M0 0.42); PSA only progression (OR yes versus non 1.93); and longer duration of MAB. Considering MAB duration of ≤9 months as reference, OR ( p) for PSA response is 1.51 (0.61) for a duration of 10–17 months; 3.87 (0.052) for a duration of 18–32 months; and 5.51 (0.011) for durations >32 months. Practically, it means that an AAW syndrome can be expected in the case of M0 CRPC after a prolonged period of MAB. In contrast, in a patient with a rapid PSA progression or extensive M+ disease despite adding a short course of second-line AA, it is unrealistic to expect PSA response and subsequent therapy should be initiated immediately.
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Table 3. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with adrenal synthesis inhibitors Total
Drug
Small et al. [48] Small et al. [49] Small et al. [50] Harris et al. [51] Millikan et al. [52] Taplin et al. [53] Sartor et al. [54] Kruit et al. [55]
Ketoconazole (400 mg tid) + hydrocortisone Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (200 mg tid) + hydrocortisone Ketoconazole (400 mg tid) + hydrocortisone + AAW Ketoconazole (400 mg tid) + dutasteride + hydrocortisone Aminoglutethimide (450 mg bid) + AAW + hydrocortisone Aminoglutethimide (1000 mg sid) + AAW + hydrocortisone
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
50 20 128 28 45 57 29 38
63 55 27 46 31 56 48 37
3.5 8.5 8.6 7.5 NR 20 4 9
% PSA response, % of patients achieving 50% decrease in PSA; AAW, antiandrogen withdrawal; NR, not reported.
Total
Drug
Smith et al. [56] Oh et al. [57] Oh et al. [57] Oh et al. [58] Small et al. [59] Pfeifer et al. [60] Osborn et al. [61] Dawson et al. [62] Fossa et al. [63]
DES (1 mg sid) DES (3 mg sid) PC-SPES (3 caps) PC-SPES (6 caps) PC-SPES (9 caps) PC-SPES (9 caps) Megestrol acetate (160–320 mg sid) Megestrol acetate (160versus 640 mg sid) Medroxyprogesterone (1 g. Sid)
Patients (n)
% Prostate-specific antigen (PSA) response
Duration (months)
21 42 43 23 37 16 14 149 21
43 24 40 52 54 81 14 12 30
NA 3.8 NA 2.5 4.0 NR NR NR 2–7
% PSA response, % of patients achieving 50% decrease in PSA; DES, diethylstilbestrol; NR, not reported.
Table 5. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with steroids Total
Drug
Tannock et al. [64] Sartor et al. [44] Fossa et al. [44] Fossa et al. [65] Kelly et al. [66] Kantoff et al. [67] Small et al. [68] Saika et al. [69] Morioka et al. [70] Storlie et al. [71] Venkitaraman et al. [72] Debruyne et al. [47]
Prednisone (7.5–10 mg sid) Prednisone (10 mg bid) Prednisone (5 mg bid) Prednisolone (10 mg bid) Hydrocortisone (40 mg qd) Hydrocortisone (30/10 mg qd) Hydrocortisone (40 mg qd) Dexamethasone (1.5 mg sid) Dexamethasone (1.5 mg sid) Dexamethasone (0.75 mg bid) Dexamethasone (0.5 mg qd) Lyarozole (300 mg bid)
Patients (n)
Prostate-specific antigen (PSA) response
Duration (months)
81 29 101 50 30 78 230 19 27 38 102 160
22 34 21 26 20 14 16 28 59 61 49 20
4 2.0 4.2 4 4 2.3 2.3 NR NR NR 7.4 NR
% PSA response, % of patients achieving 50% decrease in PSA; NA, not available.
manipulation, the clinical data are scarce. Tables 2–5 report exclusively the results of the phase II trial reporting modest PSA decrease for short duration. There is no reported phase III trial. Objective responses are seldom reported and, so far, with the exceptions of novel agents abiraterone and MDV3100, there has never been published reports of OS benefit. Noteworthily, the benefit of adding an antiandrogen to a GnRH agonist seems primarily linked to the ability of that GnRH agonist to effectively suppress testosterone and to the
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importance of androgens secretion by the adrenals. Hashimoto et al. have investigated whether serum testosterone predicted the efficacy of second-line bicalutamide or flutamide [25]. PSA response ≥50% was observed in 77.3% and 37.5% of patients with a testosterone ≥ or <5 ng/dl (P = 0.04), respectively. In addition, a testosterone <5 ng/dl was an independent factor to predict PSA PFS; 1-year PSA PFS was 52.9% versus 0% in patients with a testosterone ≥ or <5 ng/dl (P 0.002), respectively. Narimoto et al. have examined the effects of
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Table 4. Trials evaluating second-line hormonal treatment of castration-resistant prostate cancer (CRPC) with estrogen and derivatives
Annals of Oncology
flutamide as a second-line antiandrogen in 16 CRPC patients initially treated with bicalutamide [26]. A PSA decline ≥50% was observed in 50% of the patients with a median response of 6.25 months. An elevated baseline androstenediol level was a predictive factor of PSA response and a low DHEA group a predictor of a prolonged response.
epidemiology and kinetics of metastatic progression in M0 CRCP
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941 M0 CRPC with ETA atrasentan [7]. More stringent PSA kinetic parameters were requested. The PSA levels had to be at least 20 ng/ml within 12 months, or had increased by 50% within 6 months (minimum, 1 ng/ml at screening), or had been rising (two sequential increases with a confirmatory third increase) within 12 months (minimum, 1 ng/ml at screening). As a result of this selection, the mean (±SD) PSA DT was 5.9 (±3.62) months versus 9.7 (±4.7) months in the ZOL trials [7, 27]. Smith et al. have reported the data of the 331 men in the placebo group [28]. At 2 years, 46% of subjects had developed bone metastases, and 20% had died. The median BM-PFS was 25 months. In multivariate analyses, baseline PSA < 13.1 ng/ml was associated with shorter OS (RR 2.34; 95% CI 1.71–3.21; P < 0.0001), time to first bone metastasis (RR 1.98; 95% CI 1.43–2.74; P < 0.0001), and BM-PFS (RR 1.98; 95% CI 1.45–2.70; P < 0.0001). PSA velocity was significantly associated with OS and BM-PFS. Other covariates were not consistently associated with clinical outcomes. In contrast to the ZOL trial, patients were followed by 99mTC BS and CT or MRI, which allow testing the distribution of metastatic sites. Looking at the placebo cohort, progression was reported in 56.3% of the patients. Extra-skeletal lesions were cited as the primary metastatic manifestation of disease progression in only 8% of the patients, while skeletal lesions were cited as the primary metastatic progression in 44.3% of the patients. This confirmed that in approximately one patient out of five, the first metastatic site is the skeleton. The third trial was conducted by Smith et al. and has investigated the benefit of denosumab, in 1432 M0 CRCP patients [29]. The inclusion criteria specifically required a baseline PSA ≥ 8.0 ng/ml or a PSA DT ≤10.0 months, or both. Patients were followed by 99mTC BS, extraskeletal progression being only recorded by investigators. The median BM-PFS survival was 25.2 months in the placebo arm. Further sub-analyses have been reported with the aim of identifying subsets of higher-risk M0 CRPC patients who would benefit from the treatment [30]. The median BM-PFS are 22.4 months in patients with a PSA DT ≤ 10 months, 18.7 months in patients with a PSA DT ≤ 6 months, and 18.3 months in patients with a PSA DT ≤ 4 months. These studies pinpoint at three important messages. The first one is a confirmation that the skeleton is by far the first metastatic site in advanced CRPC. This provides a strong rationale for developing newer and better imaging modalities to assess the extent and progression of bone metastasis and to test earlier use of bone-targeted agents. Second, they suggest that the M0 CRCP is a heterogeneous population that overall progresses slowly, with median BMF PFS longer than 2 years. Considering the potential toxic effect of most of the available agents, this sounds as a plea to recommend active surveillance of these patients and not rely on their anxiety to anticipate, without strong rational, prescription of agents registered in metastatic patients. Finally, they confirm that PSA kinetics, and especially PSA DT, is the most useful parameter in the day-today life to counsel the patients and schedule the imaging tests.
the ‘Holy Grail’ of metastasis prevention M0 CRPC is a health state where most patients are usually strictly asymptomatic, but for the side-effects of ADT. In the
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The exact proportion of patients having CRPC before developing metastases is presently unknown. One of the explanations is the lack of clear recommendation regarding frequency and modality of imaging. Because physicians follow these patients with PSA, M0 CRPC occurs almost consistently first. Very few good quality surveys exist on the topic. Three prospective trials have investigated the potential benefit of bone-targeted agents ZOL, atrasentan, and denosumab on the development of metastases and especially bone metastases in M0 CRPC patients. Beyond the results, these data have provided a good epidemiological background to better characterize the risk of progression in that heterogeneous population. Smith et al. have conducted a randomized, doubleblind, placebo-controlled trial to evaluate the effects of ZOL on time to first bone metastasis in men with M0 CRPC defined by a rising PSA despite ADT [27]. The study was terminated before completion of accrual after an interim analysis demonstrated that the observed event rate was lower than expected. CT were not carried out, only 99mTC BS, so that this study provides information only on the rate and risk factor of bone metastases in the 201 patients from the placebo group [27]. The first observation was that the median bone metastasis PFS (BM-PFS) time was 30 months, much longer than expected. At 2 years, only 33% of patients had developed bone metastases and median time to first bone metastases and median OS were not reached. The inclusion criteria did not restrict entry in the trial to patients with a minimum PSA doubling time (DT). PSA progression was simply defined as three consecutive rises in serum PSA measured at least 2 weeks apart with an initial PSA rise within 10 months of study entry, and a last PSA ≥ 150% blood cell count nadir value. Patients with an intact prostate had a PSA level <4 ng/ml and those with radical prostatectomy had a PSA level <0.8 ng/ml. This study has helped us to understand the determinant of progression to bone metastases. The baseline PSA level <10 ng/ml [relative risk (RR) 3.18; 95% CI 1.74–5.80; P < 0.001] and PSA velocity (RR 4.34 for each 0.01 increase in PSA velocity; 95% CI 2.30–8.21; P < 0.001) independently predicted shorter time to first bone metastasis and OS. Tertiles of PSA (<7.7, 7.7 to 24, >24 ng/ml) and PSA DT (<6.3, 6.3 to 18.8, >18.8 months) were associated with different BM-PFS (P < 0.001). Other standard parameters of PCa aggressiveness did not predict the time to first bone metastases, including prior prostatectomy, Gleason sum >7, regional lymph node metastases at diagnosis, time from ADT to randomization >2 years, and time from diagnosis to randomization. With that information available, Nelson et al. have conducted a similar double blind, placebo-controlled trial in
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Table 6. Summary of bone metastasis prevention trial in M0 PCa patients treated with androgen deprivation therapy (ADT) Study
Patients
Treatment arms
Selected end-points
MRC PR04 [31, 73]
T2−4
Clodronate versus placebo
Zometa 703 [27]3
Castration-resistant prostate cancer (CRPC) T2a (Gleason ≥ 7,PSA ≥ 10 ng/ml); or T2b−4, N0 High-risk patients starting ADT
ZOL versus placebo
Time to symptomatic BM or Primary not met PCa death, OS Time to first BM, OS, BM-PFS Terminated early
EBRT + ADT ± ZOL
PSA PFS, OS, BM-PFS
Ongoing
OS, QoL, SREs, PFS
Ongoing
BM rate, OS, PSA DT BM-PFS, PSA PFS, OS, BMPFS, PSA DT PFS, OS
Ongoing Primary not met
RADAR [74]4 STAMPEDE [75]5 ZEUS [76]6 M00–244 [7]
ZOL versus docetaxel versus celecoxib, Gleason 8−10; pN+ or PSA ≥ 20 ng/ml ZOL versus standard treatment CRPC Atrasentan versus placebo
Enthuse M0 [34]8
CRPC
Zibotentan versus placebo
Results/status
Terminated early
denosumab prevention trial, serious adverse events in the placebo arm were rare [29]. Therefore, it has become as a major challenge to delay as long as possible this health state by delaying the onset of the first bone metastasis. Several trials have taken that challenge (Table 6). In addition to the aforementioned trial with ZOL, Mason et al. have conducted a randomized double-blind placebo-controlled trial to test the efficacy of oral bisphosphonate clodronate in 508 nonmetastatic PCa patients at high risk of developing bone metastases [31]. These patients were not M0 CRPC strictly speaking but patients receiving clodronate as adjuvant to ADT (stage T2–T4, N0, N+ or NX, M0). After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of BM-PFS. Three other trials are ongoing, all testing adjuvant ZOL in high-risk M0 patients receiving ADT. ETA inhibitors have been identified in the mid nineties as key mediators of bone metastases in PCa. Two agents have been tested, atrasentan and zibotentan, both suggesting promising results in phase II trials, generating a worldwide enthusiasm [32, 33]. Two large phases III have been initiated in the M0 CRPC setting with the ambitious end-points of prolonging time to first bone metastasis but also OS. The primary was not met for the atrasentan trial and the independent data monitoring committee prematurely closed the zibotentan trial [7, 34]. Smith et al. have recently reported the results of a randomized, placebo-controlled trial testing denosumab in 1432 M0 CRPC patients. In that patient population with a PSA ≥ 8 ng/ml and/or a PSA DT ≤ 10 months, denosumab significantly increased BM-PFS by a median of 4.2 months compared with placebo. The median BM-PFS was 29.5 (95% CI 25.4–33.3) months in patients receiving denosumab versus 25.2 (95% CI 22.2–29.5) in patients receiving placebo; the hazard ratio (HR) for BM-PFS is 0.85 (95% CI 0.73–0.98, P = 0.028). OS did not differ between patients receiving early denosumab and placebo. The rates of adverse events and serious adverse events were similar in both the groups, except for osteonecrosis of the jaw (5% in denosumab versus 0% in
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placebo) and hypocalcemia (2% in denosumab versus <1% on placebo). Although that trial is the first to demonstrate that interfering with the physiology of the bone microenvironment can delay bone metastasis in men with PCa, it is under extensive discussion. On one hand, we must acknowledge that this is a major proof-of-concept on the role of RANK-L in the development of bone metastases. Clinically speaking however, we must still understand the relevance and impact of delaying metastases by 4 months on the natural history of the disease. The major limitation indeed is that no recommendation was made on pursuing denosumab after bone metastases progression. As a result, data are not available on the impact on delaying SRE or symptoms. In the absence of even a trend on OS, our reading of the clinical impact is clearly limited. Attempts have been made to identify a subset of patients in which denosumab would confer a higher benefit on BMF survival [30]. As mentioned earlier, BM-PFS decreases with lower PSA DT cut-offs. Interestingly, the benefit of denosumab increases in these subsets of patients. Denosumab increases BM-PFS survival by 6.0 months in patients with a PSA DT ≤ 10 months (HR = 0.85; P = 0.028), by 7.2 months in patients with a PSA DT ≤ 6 months (HR = 0.77; P = 0.006), and by 7.5 months in patients with a PSA DT ≤ 4 months (HR = 0.71; P = 0.004). Of note, these subsets of patients represent 81%, 59.1%, and 39% of the study population, respectively.
conclusion The introduction of early PSA-based diagnosis has impacted the epidemiology of CRPC. Many patients nowadays enter the disease at an early stage when the only sign of resistance to ADT is a progressive elevation of PSA. Physicians confronted to these patients should recognize three important facts. First, although the disease remains largely driven by the AR, the benefit of second-line hormonal manipulations, including first generation antiandrogens, adrenal synthesis inhibitors, steroids and estrogens, is clearly limited. There are no data indicating a clear benefit beyond PSA response. Now that several drugs are available to effectively treat CRPC, the rationale for prescribing
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BM, bone metastasis; BM-PFS, bone metastasis progression-free survival; EBRT, external beam radiotherapy; PFS, progression-free survival; ZOL, zoledronic acid; DT, doubling time; OS, overall survival; QoL, quality of life; SRE, skeletal-related event; PSA, prostate-specific antigen. STAMPEDE includes M0 and M+ patients.
Annals of Oncology
these drugs should be revisited. Second, physicians following CRPC should recognize that M0 CRPC is an extremely heterogeneous stage of the disease, with most patients progressing slowly to a metastatic stage. Currently, the kinetics of PSA progression appear to be the best indicator of progression and the optimal tool to identify high-risk patients. Finally, and most importantly, physicians should acknowledge that the available registered treatments have been studied in far more advanced stage of the disease. There is absolutely no evidence that the efficacy/toxic effect profile is preserved if these drugs are prescribed at a much earlier stage of the disease. This will have to be kept in mind, especially in face of the development of more sensitive imaging techniques.
disclosure
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15. Schroder FH, Tombal B, Miller K, Boccon-Gibod L, Shore ND, Crawford ED et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106(2): 182–187. 16. Labrie F, Dupont A, Belanger A. Complete androgen blockade for the treatment of prostate cancer. Important Adv Oncol 1985: 193–217. 17. Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002; 95(2): 361–376. 18. Schmitt B, Bennett C, Seidenfeld J, Samson D, Wilt TJ. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 1999(2): CD001526. 19. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000; 355(9214): 1491–1498. 20. Klotz L, Schellhammer P. Combined androgen blockade: the case for bicalutamide. Clin Prostate Cancer 2005; 3(4): 215–219. 21. Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy. Eur Urol Suppl 2008; 7(1): 15–21. 22. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 2007; 178(4 Pt 1): 1290–1295. 23. Lawrentschuk N, Fernandes K, Bell D, Barkin J, Fleshner N. Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. J Urol 2011; 185(3): 848–854. 24. Sartor AO, Tangen CM, Hussain MH, Eisenberger MA, Parab M, Fontana JA et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer 2008; 112(11): 2393–2400. 25. Hashimoto K, Masumori N, Hashimoto J, Takayanagi A, Fukuta F, Tsukamoto T. Serum testosterone level to predict the efficacy of sequential use of antiandrogens as second-line treatment following androgen deprivation monotherapy in patients with castration-resistant prostate cancer. Jpn J Clin Oncol 2011; 41(3): 405–410. 26. Narimoto K, Mizokami A, Izumi K, Mihara S, Sawada K, Sugata T et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a secondline anti-androgen. Int J Urol 2010; 17(4): 337–345. 27. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 23(13): 2918–2925. 28. Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer 2011: 117(10): 2077–2085. 29. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379(9810): 39–46. 30. Smith M, Saad F, Shore N, Oudard S, Miller K, Tombal B et al. Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics. J Clin Oncol 2012; 30(suppl 5) (Abstr 6). 31. Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, Sokal M et al. Oral sodium clodronate for nonmetastatic prostate cancer–results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007; 99(10): 765–776. 32. Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003; 21(4): 679–689. 33. James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol 2009; 55(5): 1112–1123.
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BT is an investigator or a consultant for Astellas, Amgen, Ferring, Medivation, Janssens, Sanofi-Aventis.
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