- Email: [email protected]
A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer
Annals of Oncology Advance Access published December 3, 2007
original article
Annals of Oncology doi:10.1093/annonc/mdm554
A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer K. N. Chi1*, S. L. Ellard2, S. J. Hotte3, P. Czaykowski4, M. Moore5, J. D. Ruether6, A. J. Schell7, S. Taylor7, C. Hansen8, I. Gauthier8, W. Walsh8 & L. Seymour8 1
Background: The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. Patients and methods: This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) ‘response’ defined as a ‡50% decrease for ‡4 weeks. Results: In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1–8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 lg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8–6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%–52%. Conclusions: Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response. Key words: phase II clinical trial, prostate cancer, prostate-specific antigen, sorafenib
introduction Prostate cancer is the most common cancer diagnosed and the third most common cause of cancer death in men in North America [1]. Patients with metastatic disease have a poor prognosis, and although hormonal therapy in the form of medical or surgical castration can induce significant long-term remissions, development of androgen-independent disease is inevitable. Androgen-independent disease, also termed hormone-refractory or castration-resistant prostate cancer, is clinically detected by a rise in prostate-specific antigen (PSA) and/or worsening of symptoms. The current standard of care for castration-resistant prostate cancer is palliative in its intent, and includes analgesia, radiation, bisphosphonates, and chemotherapy such as mitoxantrone or docetaxel, with only the last treatment being associated with an overall survival (OS) benefit [2]. With the early commencement of androgen *Correspondence to: Dr K. N. Chi, Vancouver Centre, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. Tel: +1-604-877-6000; Fax: +1-604-877-0585; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
deprivation therapy and frequent use of PSA for monitoring disease progression, an increasing population of patients with castration-resistant disease is now more commonly identified by a rising PSA rather than by new disease or symptoms. Early intervention with chemotherapy is of unknown benefit in these patients, and thus represents an appropriate group for phase II ‘window’ studies to evaluate novel agents with acceptable toxicity profiles. Several mechanisms of androgen-independent progression have been proposed [3]. Activation of growth factor receptor pathways, such as through Her-2, insulin-like growth factor 1 and epidermal growth factor, is one such mechanism that can lead to androgen-independent growth and ligand-independent activation of the androgen receptor [4–6]. Raf kinases are central regulators of mitogenic signaling pathways connecting upstream growth factor-mediated receptor tyrosine kinase stimulation with downstream activation of the mitogenactivated protein kinase (MAPK) pathway and subsequent cellular effects, and thus inhibition of raf kinases is a potential therapeutic target. Another therapeutic approach is to interfere
original article
Received 14 September 2007; revised 2 November 2007; accepted 5 November 2007
Downloaded from http://annonc.oxfordjournals.org/ at California State University, Fresno on July 8, 2015
Department of Medical Oncology, Vancouver Centre, BC Cancer Agency, Vancouver, British Columbia; 2Department of Medical Oncology, Centre for the Southern Interior, BC Cancer Agency, Kelowna; 3Department of Medical Oncology, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton; 4Department of Medical Oncology, Cancer Care Manitoba, Winnipeg; 5Department of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto; 6Department of Medical Oncology, Tom Baker Cancer Centre, Calgary; 7Department of Pathology and Molecular Medicine, Queen’s University, Kingston; 8IND Program, National Cancer Institute of Canada–Clinical Trials Group, Kingston, Canada
original article
patients and methods
end points were measurable disease response rate and duration of response as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria [13]. Cases where discordance between PSA response and objective evaluation occurred were to be noted. Patients who had objective progression or PSA progression were considered treatment failures. Using a response rate of <5% for the null hypotheses versus an alternate hypothesis response rate of >20%, 15 assessable patients were planned to be entered in the first stage. If ‡1 response was observed, an additional 10 patients were to be accrued. Sorafenib would be considered of interest for this indication if three or more PSA responses were observed in the 25 patients accrued. With this design, the significance level was a = 0.12 and the power 0.89. Sorafenib was administered orally at a starting dose of 400 mg twice daily continuously on a 4-week cycle. Doses were decreased for toxicity: first dose reduction to 200 mg twice daily and second dose reduction to 200 mg twice daily for 3 weeks out of 4. Patients requiring a third dose reduction were removed from protocol therapy. All patients underwent a baseline history and physical exam, investigations including PSA, hematology, coagulation, biochemistry, liver, and renal function studies, and restaging evaluations with bone scan and computed tomography (CT) scans of the abdomen and pelvis. PSA was repeated every 4 weeks and bone and CT scans repeated after every two cycles if they were initially positive for metastases. Patients were seen at 4 weeks after completion of protocol therapy. Thereafter, follow-up was not required for patients who went off protocol treatment with progressive disease, while those without progression were followed every 3 months until progression. Adverse events were graded according to the Common Toxicity Criteria for Adverse Events, version 3.0.
patient population
correlative studies
To be eligible, patients must have had a pathologic diagnosis of adenocarcinoma of the prostate, have recurrent disease with a PSA ‡10 lg/l at the time of study entry, and documented evidence of PSA progression despite castrate levels of testosterone and after discontinuation of peripheral antiandrogens. Evidence of PSA progression was defined as a ‡25% increase (minimum 5 lg/l) over a reference value, confirmed by a second increase in PSA at least 1 week later. Prior chemotherapy was not permitted; however, prior use of radiation and corticosteroids were allowed. Patients were required to have an Eastern Cooperative Oncology Group performance status of zero to one and adequate organ function [neutrophils ‡ 1.5 · 109/l, platelets ‡ 100 · 109/l, bilirubin and creatinine within normal limits or creatinine clearance ‡ 60 ml/min, and aspartate transaminase (AST) and alanine transaminase £ 2.5 · upper limit normal]. Patients were excluded if they had a history of other malignancies except adequately treated nonmelanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ‡5 years, if they had brain metastases or other serious intercurrent illness. Patients who required large amounts of narcotic therapy to control pain (e.g. morphine equivalent dose >30 mg/day) were excluded. Written informed consent was obtained from all patients. The study was approved by the institutional review boards of all participating centers.
The purpose of the correlative studies was to explore associations between expression of putative molecular markers in a patient’s primary tumor specimen and antitumor activity of sorafenib. All patients enrolled to the study had representative sections from the paraffin block of their primary tumor diagnostic specimen evaluated. Activating mutations have been observed in exons 11 and 15 of the BRAF gene including V599E, which accounts for 80% of observed BRAF mutations in human cancers [14]. Polymerase chain reaction (PCR) was used to amplify exons 11 and 15 of the BRAF gene in DNA extracted from archived tumor samples followed by denaturing high-performance liquid chromatography (DHPLC) to screen for the presence or absence of mutations [15]. DNA from normal individuals and cell lines with known BRAF gene mutations were used as assay controls. Epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R), extracellular signal-regulated kinase 2 (ERK), phosphorylated-ERK, and VEGFR-2 expression were assessed by immunohistochemical staining using standard peroxidase–antiperoxidase techniques. Staining intensity in invasive tumor cells was determined by two observers using a three-point scale: 0 = no staining seen, 1 = weak staining intensity and/or <20% of tumor cells stained, and 2 = strong staining in >20% of tumor cells.
study design
statistical analyses
This was a single-arm, open-label, multicenter, two-stage [11], phase II study conducted by the National Cancer Institute of Canada Clinical Trials Group. The primary end point of the study was PSA ‘response’ defined as a 50% decline in PSA (minimum 5 lg/l) from baseline maintained for ‡4 weeks and without evidence of disease progression otherwise [12]. PSA progression in PSA nonresponders was defined as a rise in PSA of 25% (minimum 5 lg/l) above baseline value and confirmed by a second increasing value at least 1 week later. In PSA responders, PSA progression was defined as a rise in PSA of 50% (minimum 5 lg/l) above nadir value and confirmed by a second increasing value at least 1 week later. Secondary
The Kaplan–Meier method was used to estimate the median time to PSA progression, time to treatment failure, and OS and associated confidence intervals (CIs). Fisher’s exact test was used to assess the relationship between immunohistochemistry scores for EGFR, IGF1R, ERK, phosphorylated-ERK, and VEGFR-2 and baseline clinical factors, which included age (£60 versus >60 years), performance status (0 versus 1), Gleason score (6 or 7 versus 8 or 9), time from diagnosis of disease to registration on the trial (<6 years versus ‡6 years), and liver metastases (yes versus no), or PSA changes during or after protocol therapy with sorafenib.
2 | Chi et al.
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with the ability of a cancer to promote vascularization as an important process in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) receptors 1 and 2 are expressed in animal models and clinical samples of prostate cancer, with vascular endothelial growth factor receptor (VEGFR)-2 expression being associated with progression and more poorly differentiated tumors [7]. Furthermore, inhibition of VEGFR-2 activity reduces tumorigenicity and metastases in xenograft models of prostate cancer [8]. Elevated levels of VEGF have been noted in patients with advanced prostate cancer and this has been associated with poor prognosis in castration-resistant disease [9]. Sorafenib is an orally bioavailable kinase inhibitor initially identified by its activity against BRAF. Sorafenib is active at nanomolar concentrations against a number of kinases including c-raf, BRAF, VEGFR, platelet-derived growth factor receptor, Flt-3, c-KIT, and RET. Sorafenib has broad spectrum in vivo activity against a number of tumor types, and has proven clinical efficacy in patients with metastatic renal cell carcinoma [10]. This activity, taken together with the evidence linking progression of prostate cancer and activation of growth factor signaling pathways through raf and angiogenesis through VEGFR, provided a rationale to study the antitumor activity of sorafenib in patients with castration-resistant prostate cancer.
Annals of Oncology
original article
Annals of Oncology
results patient characteristics Twenty-eight patients were enrolled from July 2004 to December 2005, with the first stage accruing from June 2004 to November 2004 and the second stage from August to December 2005. All 28 patients were assessable for adverse events, 27 were assessable for PSA response, and 8 had evaluable measurable disease. Median age was 67 years (range 49–84 years); no patients had received prior chemotherapy, and 26 patients had evidence of local and/or metastatic disease with two patients having only rising PSA as evidence of disease. Patient baseline characteristics are listed in Table 1.
Table 1. Patient characteristics Characteristics Age Time from diagnosis Gleason score 6 or 7 8 or 9 Unknown Performance status 0 1 Prior therapy Hormonal therapy Radiotherapy Chemotherapy Other Albumin (g/l)
Number of patients (N = 28)
adverse events In general, protocol therapy was well tolerated with adverse events attributed to sorafenib being similar to what have been previously described [10]. The majority of missed or reduced doses were due to grade 2 or 3 hand–foot syndrome, rash, and/ or fatigue. The most common adverse events included fatigue (54% of patients), skin rash (50%), hand–foot syndrome (39%), anorexia (36%), diarrhea (32%), and heartburn (32%). These were grade 1–2 in severity with the exception of one patient experiencing grade 3 fatigue and two with grade 3 hand–foot syndrome. One patient had grade 3 neutropenia on study, and an additional patient had grade 3 neutropenia 28 days after discontinuing sorafenib and receiving radiation. Laboratory adverse events have been mild. In patients with
Median (range) 67 (49–84) years 67.2 (19–171) months
Table 2. Adverse events attributed to be at least possibly related to protocol therapy, occurring in >10% of patients Adverse event
10 11 7 19 9 28 18 0 1 39 (29–47) 2 26 133 28 0 22 13 3 3 2 2 4 2 16 4 5 1
Grade
Number of patients—worst by grade (N = 28) 1 2
Hand–foot syndrome Increased AST Granulocytopenia Fatigue Lymphopenia Anemia Leukocytopenia Hypertension Hypoalbuminemia Skin rash Increased bilirubin Platelets Taste alteration Increased ALT Dry skin Mucositis Abdominal pain Anorexia Heartburn Pruritis Vomiting Sensory neuropathy Fever Diarrhea Constipation Nausea Creatinine Alopecia Throat pain
4 7 2 9 5 15 5 1 2 10 3 8 5 5 4 4 4 9 8 5 4 4 2 9 7 6 5 5 3
5 3 0 5 5 2 1 1 5 4 4 2 2 2 2 2 2 1 1 1 1 1 1
3 2 2 2 1 1 1 1 1
AST, aspartate transaminase; ALT, alanine transaminase.
doi:10.1093/annonc/mdm554 | 3
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treatments administered Median number of cycles delivered was two (range 1–8). Fifteen patients discontinued protocol therapy because of rising PSA, five because of progressive disease, two patients refused further treatment, four for other reasons, and one patient discontinued
therapy because of hematologic adverse events with grade 3 anemia and grade 2 thrombocytopenia. Fifty-seven percent of patients received ‡90% of planned dose intensity. Nineteen patients missed at least one dose with 75% of missed doses being due to an adverse event, four had dose delays, eight had dose reductions, and one patient had an increase in dose after an initial dose reduction for hand–foot syndrome.
original article
Annals of Oncology
normal baseline chemistries, these have been grade 1–2 in severity with the exception of one patient experiencing grade 3 elevated AST. Table 2 lists adverse events considered at least possibly related to protocol therapy.
Percentage Change in PSA from Baseline
Figure 1. Plot of greatest percentage change in prostate-specific antigen (PSA) of individual patients while on protocol therapy for all patients.
progression-free survival and OS. Median time to PSA progression was 2.1 months (95% CI 1.8–6.4) (Figure 3) and time to treatment failure was 1.8 months (95% CI 1.7–2.8). OS was 12.25 months (95% CI 6.7–16.46). PSA declines after discontinuation of sorafenib. There were 26 patients with PSA data available for analysis of PSA change after discontinuation of protocol therapy. Sixteen patients had not received any immediate treatment after discontinuing sorafenib and 10 of these patients had a PSA decline of 7%–52% (as compared with the last PSA while on sorafenib therapy). Ten patients received immediate therapy after discontinuing sorafenib: four patients received palliative radiation, three received corticosteroids 6 ketoconazole, two received treatment with chemotherapy (mitoxantrone and docetaxel) and one was given a nonsteroidal antiandrogen. Of these 10 patients, 8 had a PSA decline of 14%–91%.
correlative studies BRAF mutation. PCR amplification was successful in 13 of 26 cases for BRAF exon 11 and 14 of 26 cases for BRAF exon 15. DHPLC analysis revealed a single case in which five unclassified Time to PSA Proression
800
100
700 80
600 500
60
400
% 40
300 200
20
100 0
0 0
10
20
30
40
Weeks Figure 2. Plot of percentage change in prostate-specific antigen (PSA) of individual patients over time while on protocol therapy.
4 | Chi et al.
0.0 At Risk: 27
2.0 14
4.0 6
6.0 1
Time (Months) Figure 3. Time to prostate-specific antigen (PSA) progression.
8.0 0
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antitumor activity PSA declines. In the first stage of accrual for the study, one patient experienced a post-treatment PSA decline of ‡50% that was confirmed 4 weeks later. The baseline PSA in this patient was 10 000 lg/l and decreased to a nadir level of 1643 lg/l, with a time to PSA progression of 2.82 months. No patients accrued in the second stage had a post-treatment PSA decline of ‡50%. The PSA response rate among all assessable patients was 3.6% (95% CI 0.1% to 18.3%). Five patients experienced PSA declines of <50%: two had declines of 25%–49% and three had declines of <25%. The greatest percentage change in PSA while on protocol therapy for all patients is depicted in Figure 1. Figure 2 plots change in PSA for individual patients over time while on protocol therapy. Several patients had an initial increase in PSA which was followed by an apparent decline or stabilization, however, protocol-mandated procedures required discontinuation of these patients from sorafenib therapy because of that initial PSA rise.
measurable disease responses. Twelve patients were enrolled with measurable disease. Five of the patients had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) as their best objective response, three had progressive disease, and four were inevaluable [response rate = 0% (95% CI 0% to 31.2%)]. Sixteen patients had nonmeasurable disease only; three had a best response of progression (increasing lesions on bone scan) while the other 13 were inevaluable by RECIST criteria response or progression. For patients who went off protocol therapy after meeting PSA progression criteria, eight had measurable disease and two of these patients had stable disease and four had progressive disease by RECIST criteria at the time of sorafenib discontinuation. Of the other 13 patients, 5 had nonmeasurable disease and 5 had met RECIST criteria for disease progression at the time of sorafenib discontinuation.
original article
Annals of Oncology
variants were identified in exon 15, none of which have been previously reported to activate BRAF. This patient had an increasing PSA as best PSA response. immunohistochemistry. Twenty-five patients had sufficient tissues for analysis (Figure 4). There were no statistically significant correlations between immunohistochemistry scores for EGFR, IGF1R, ERK, phosphorylated-ERK, and VEGFR-2 and baseline clinical factors (age, performance status, Gleason score, time from diagnosis of disease to registration of the study, and liver metastases) or PSA changes during or after protocol therapy with sorafenib.
discussion
100
Percentage of Cases
90 80 70 60 50 40 30 20 10 0 0 1 2 VEGFR2
0 1 2 ERK
0 1 2 P-ERK
0 2 1 IGF1R
0 1 2 EGFR
Immunohistochemistry Scoring Figure 4. Immunohistochemistry scoring in primary tumor biopsies for vascular endothelial growth factor receptor-2 (VEGFR-2), ERK, phosphorylated-ERK, insulin-like growth factor 1 receptor (IGF1R), and epidermal growth factor receptor (EGFR).
funding National Cancer Institute of Canada, Canadian Cancer Society.
acknowledgements Sorafenib was provided by the National Cancer Institute Cancer Therapy Evaluation Program.
doi:10.1093/annonc/mdm554 | 5
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Progression of prostate cancer to androgen independence has been associated with a number of processes including activation of growth factor signaling pathways [3]. Several agents targeting these pathways have been tested but despite encouraging preclinical data, clinical results have been disappointing [16, 17]. In this study, we evaluated the multitargeted kinase inhibitor sorafenib. Using accepted criteria for reporting PSA declines on clinical trials [12], only limited activity was seen, with one notable case of a 90% decrease in PSA and five patients with lesser decreases. Closer inspection of the data indicate that some patients had an initially rising PSA while on therapy which then appeared to start stabilizing (Figure 2); however, protocol-mandated discontinuation rules required the patients to come off therapy on the basis of the initial PSA rise alone. In addition, 62% of patients were found to have a decreasing PSA after discontinuing protocol therapy with sorafenib therapy despite receiving no additional therapy. Even in those patients who did receive some sort of immediate postprotocol therapy, 80% had post-treatment PSA declines, which could be considered an unexpectedly high response rate, given the nature of the treatments received. These results delineate a number of challenges when assessing activity of targeted therapies in patients with castrationresistant prostate cancer. The first is the use and reliance on PSA as the only quantifiable measure of response and treatment failure. Although an important and useful tumor marker,
clinical benefit is not entirely reflected by PSA changes alone [18]. The observed PSA declines after withdrawal of sorafenib therapy could indicate an isolated effect on PSA production or secretion separate from sorafenib’s antitumor activity. This effect may also be transient given the initial rise in PSA seen in several patients followed by an apparent stabilization or inflection. An effect of sorafenib on PSA production/secretion is further supported by recently presented data from a study of sorafenib in patients with castration-resistant prostate cancer which included patients who had previously received chemotherapy [19]. No PSA responses were observed in that study, but cases of metastatic bone disease responding independently of PSA were noted. Preclinical studies were also presented which demonstrated an effect of sorafenib on PSA production/secretion that was separate of its cytotoxic effect [19]. Additionally, attenuation of Ras signaling has been shown to restore androgen sensitivity in hormone-refractory C4-2 prostate cancer cells [20], and thus the sorafenib associated increase in PSA could relate to increased activation of androgen receptor through inhibition of MAPK signaling pathways. This latter hypothesis raises a further therapeutic strategy that could be explored of combining growth factor signal targeting and androgen receptor inhibition. Another obstacle to study targeted therapies in patients with prostate cancer is the lack of representative malignant tissue available for correlative studies. Castration-resistant disease presents predominantly as bone metastases and is thus not amenable to convenient sampling [21]. Extrapolating expression of a particular biomarker from initial tumor biopsies of androgen-dependent disease to the castrationresistant state is potentially flawed because of the well-described gene expression shifts that occur with the emergence of androgen independence [22]. In this study, we attempted to evaluate primary tissues and correlate with baseline factors and outcomes and no associations were apparent. This could perhaps be expected given the previous caveats, small number of subjects, and limited PSA responses. One patient was identified as having five variants within exon 15 of BRAF, none of which have been previously associated with activation of BRAF, and in this case there was no association with a clinical response. The fact that PSA response may not even be a relevant end point for sorafenib further weakens this analysis. In conclusion, for patients with castration-resistant prostate cancer, sorafenib induces minimal PSA responses as defined by accepted criteria. The limitations of PSA as the primary indicator of response and progression in this setting, however, need to be considered. Additional trials are under way evaluating sorafenib in patients with castration-resistant disease, including combinations with the nonsteroidal antiandrogen bicalutamide and mitoxantrone.
original article references
6 | Chi et al.
12. Bubley GJ, Carducci M, Dahut W et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17: 3461–3467. 13. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 14. Hellawell GO, Turner GD, Davies DR et al. Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 2002; 62: 2942–2950. 15. Meyer P, Klaes R, Schmitt C et al. Exclusion of BRAFV599E as a melanoma susceptibility mutation. Int J Cancer 2003; 106: 78–80. 16. Canil CM, Moore MJ, Winquist E et al. Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol 2005; 23: 455–460. 17. de Bono JS, Bellmunt J, Attard G et al. Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 2007; 25: 257–262. 18. Petrylak DP, Ankerst DP, Jiang CS et al. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 2006; 98: 516–521. 19. Dahut WL SC, Posadas EM, Wu S et al. Bony metastatic disease responses to sorafenib (BAY 43-9006) independent of PSA in patients with metastatic androgen independent prostate cancer. ASCO Annual Meeting Proceedings. J Clin Oncol 2006; 24: (Abstr 4506). 20. Bakin RE, Gioeli D, Bissonette EA et al. Attenuation of Ras signaling restores androgen sensitivity to hormone-refractory C4-2 prostate cancer cells. Cancer Res 2003; 63: 1975–1980. 21. Scher HI, Morris MJ, Kelly WK et al. Prostate cancer clinical trial end points: ‘‘RECIST’’ing a step backwards. Clin Cancer Res 2005; 11: 5223–5232. 22. Bubendorf L, Kolmer M, Kononen J et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J Natl Cancer Inst 1999; 91: 1758–1764.
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1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130. 2. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512. 3. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001; 1: 34–45. 4. Craft N, Shostak Y, Carey M, Sawyers CL. A mechanism for hormoneindependent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 1999; 5: 280–285. 5. Culig Z, Hobisch A, Cronauer MV et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994; 54: 5474–5478. 6. Yeh S, Lin HK, Kang HY et al. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA 1999; 96: 5458–5463. 7. Huss WJ, Hanrahan CF, Barrios RJ et al. Angiogenesis and prostate cancer: identification of a molecular progression switch. Cancer Res 2001; 61: 2736–2743. 8. Sweeney P, Karashima T, Kim SJ et al. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res 2002; 8: 2714–2724. 9. George DJ, Halabi S, Shepard TF et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 2001; 7: 1932–1936. 10. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134. 11. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38: 143–151.
Annals of Oncology
original article
Annals of Oncology doi:10.1093/annonc/mdm554
A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer K. N. Chi1*, S. L. Ellard2, S. J. Hotte3, P. Czaykowski4, M. Moore5, J. D. Ruether6, A. J. Schell7, S. Taylor7, C. Hansen8, I. Gauthier8, W. Walsh8 & L. Seymour8 1
Background: The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. Patients and methods: This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) ‘response’ defined as a ‡50% decrease for ‡4 weeks. Results: In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1–8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 lg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8–6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%–52%. Conclusions: Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response. Key words: phase II clinical trial, prostate cancer, prostate-specific antigen, sorafenib
introduction Prostate cancer is the most common cancer diagnosed and the third most common cause of cancer death in men in North America [1]. Patients with metastatic disease have a poor prognosis, and although hormonal therapy in the form of medical or surgical castration can induce significant long-term remissions, development of androgen-independent disease is inevitable. Androgen-independent disease, also termed hormone-refractory or castration-resistant prostate cancer, is clinically detected by a rise in prostate-specific antigen (PSA) and/or worsening of symptoms. The current standard of care for castration-resistant prostate cancer is palliative in its intent, and includes analgesia, radiation, bisphosphonates, and chemotherapy such as mitoxantrone or docetaxel, with only the last treatment being associated with an overall survival (OS) benefit [2]. With the early commencement of androgen *Correspondence to: Dr K. N. Chi, Vancouver Centre, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. Tel: +1-604-877-6000; Fax: +1-604-877-0585; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
deprivation therapy and frequent use of PSA for monitoring disease progression, an increasing population of patients with castration-resistant disease is now more commonly identified by a rising PSA rather than by new disease or symptoms. Early intervention with chemotherapy is of unknown benefit in these patients, and thus represents an appropriate group for phase II ‘window’ studies to evaluate novel agents with acceptable toxicity profiles. Several mechanisms of androgen-independent progression have been proposed [3]. Activation of growth factor receptor pathways, such as through Her-2, insulin-like growth factor 1 and epidermal growth factor, is one such mechanism that can lead to androgen-independent growth and ligand-independent activation of the androgen receptor [4–6]. Raf kinases are central regulators of mitogenic signaling pathways connecting upstream growth factor-mediated receptor tyrosine kinase stimulation with downstream activation of the mitogenactivated protein kinase (MAPK) pathway and subsequent cellular effects, and thus inhibition of raf kinases is a potential therapeutic target. Another therapeutic approach is to interfere
original article
Received 14 September 2007; revised 2 November 2007; accepted 5 November 2007
Downloaded from http://annonc.oxfordjournals.org/ at California State University, Fresno on July 8, 2015
Department of Medical Oncology, Vancouver Centre, BC Cancer Agency, Vancouver, British Columbia; 2Department of Medical Oncology, Centre for the Southern Interior, BC Cancer Agency, Kelowna; 3Department of Medical Oncology, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton; 4Department of Medical Oncology, Cancer Care Manitoba, Winnipeg; 5Department of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto; 6Department of Medical Oncology, Tom Baker Cancer Centre, Calgary; 7Department of Pathology and Molecular Medicine, Queen’s University, Kingston; 8IND Program, National Cancer Institute of Canada–Clinical Trials Group, Kingston, Canada
original article
patients and methods
end points were measurable disease response rate and duration of response as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria [13]. Cases where discordance between PSA response and objective evaluation occurred were to be noted. Patients who had objective progression or PSA progression were considered treatment failures. Using a response rate of <5% for the null hypotheses versus an alternate hypothesis response rate of >20%, 15 assessable patients were planned to be entered in the first stage. If ‡1 response was observed, an additional 10 patients were to be accrued. Sorafenib would be considered of interest for this indication if three or more PSA responses were observed in the 25 patients accrued. With this design, the significance level was a = 0.12 and the power 0.89. Sorafenib was administered orally at a starting dose of 400 mg twice daily continuously on a 4-week cycle. Doses were decreased for toxicity: first dose reduction to 200 mg twice daily and second dose reduction to 200 mg twice daily for 3 weeks out of 4. Patients requiring a third dose reduction were removed from protocol therapy. All patients underwent a baseline history and physical exam, investigations including PSA, hematology, coagulation, biochemistry, liver, and renal function studies, and restaging evaluations with bone scan and computed tomography (CT) scans of the abdomen and pelvis. PSA was repeated every 4 weeks and bone and CT scans repeated after every two cycles if they were initially positive for metastases. Patients were seen at 4 weeks after completion of protocol therapy. Thereafter, follow-up was not required for patients who went off protocol treatment with progressive disease, while those without progression were followed every 3 months until progression. Adverse events were graded according to the Common Toxicity Criteria for Adverse Events, version 3.0.
patient population
correlative studies
To be eligible, patients must have had a pathologic diagnosis of adenocarcinoma of the prostate, have recurrent disease with a PSA ‡10 lg/l at the time of study entry, and documented evidence of PSA progression despite castrate levels of testosterone and after discontinuation of peripheral antiandrogens. Evidence of PSA progression was defined as a ‡25% increase (minimum 5 lg/l) over a reference value, confirmed by a second increase in PSA at least 1 week later. Prior chemotherapy was not permitted; however, prior use of radiation and corticosteroids were allowed. Patients were required to have an Eastern Cooperative Oncology Group performance status of zero to one and adequate organ function [neutrophils ‡ 1.5 · 109/l, platelets ‡ 100 · 109/l, bilirubin and creatinine within normal limits or creatinine clearance ‡ 60 ml/min, and aspartate transaminase (AST) and alanine transaminase £ 2.5 · upper limit normal]. Patients were excluded if they had a history of other malignancies except adequately treated nonmelanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ‡5 years, if they had brain metastases or other serious intercurrent illness. Patients who required large amounts of narcotic therapy to control pain (e.g. morphine equivalent dose >30 mg/day) were excluded. Written informed consent was obtained from all patients. The study was approved by the institutional review boards of all participating centers.
The purpose of the correlative studies was to explore associations between expression of putative molecular markers in a patient’s primary tumor specimen and antitumor activity of sorafenib. All patients enrolled to the study had representative sections from the paraffin block of their primary tumor diagnostic specimen evaluated. Activating mutations have been observed in exons 11 and 15 of the BRAF gene including V599E, which accounts for 80% of observed BRAF mutations in human cancers [14]. Polymerase chain reaction (PCR) was used to amplify exons 11 and 15 of the BRAF gene in DNA extracted from archived tumor samples followed by denaturing high-performance liquid chromatography (DHPLC) to screen for the presence or absence of mutations [15]. DNA from normal individuals and cell lines with known BRAF gene mutations were used as assay controls. Epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R), extracellular signal-regulated kinase 2 (ERK), phosphorylated-ERK, and VEGFR-2 expression were assessed by immunohistochemical staining using standard peroxidase–antiperoxidase techniques. Staining intensity in invasive tumor cells was determined by two observers using a three-point scale: 0 = no staining seen, 1 = weak staining intensity and/or <20% of tumor cells stained, and 2 = strong staining in >20% of tumor cells.
study design
statistical analyses
This was a single-arm, open-label, multicenter, two-stage [11], phase II study conducted by the National Cancer Institute of Canada Clinical Trials Group. The primary end point of the study was PSA ‘response’ defined as a 50% decline in PSA (minimum 5 lg/l) from baseline maintained for ‡4 weeks and without evidence of disease progression otherwise [12]. PSA progression in PSA nonresponders was defined as a rise in PSA of 25% (minimum 5 lg/l) above baseline value and confirmed by a second increasing value at least 1 week later. In PSA responders, PSA progression was defined as a rise in PSA of 50% (minimum 5 lg/l) above nadir value and confirmed by a second increasing value at least 1 week later. Secondary
The Kaplan–Meier method was used to estimate the median time to PSA progression, time to treatment failure, and OS and associated confidence intervals (CIs). Fisher’s exact test was used to assess the relationship between immunohistochemistry scores for EGFR, IGF1R, ERK, phosphorylated-ERK, and VEGFR-2 and baseline clinical factors, which included age (£60 versus >60 years), performance status (0 versus 1), Gleason score (6 or 7 versus 8 or 9), time from diagnosis of disease to registration on the trial (<6 years versus ‡6 years), and liver metastases (yes versus no), or PSA changes during or after protocol therapy with sorafenib.
2 | Chi et al.
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with the ability of a cancer to promote vascularization as an important process in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) receptors 1 and 2 are expressed in animal models and clinical samples of prostate cancer, with vascular endothelial growth factor receptor (VEGFR)-2 expression being associated with progression and more poorly differentiated tumors [7]. Furthermore, inhibition of VEGFR-2 activity reduces tumorigenicity and metastases in xenograft models of prostate cancer [8]. Elevated levels of VEGF have been noted in patients with advanced prostate cancer and this has been associated with poor prognosis in castration-resistant disease [9]. Sorafenib is an orally bioavailable kinase inhibitor initially identified by its activity against BRAF. Sorafenib is active at nanomolar concentrations against a number of kinases including c-raf, BRAF, VEGFR, platelet-derived growth factor receptor, Flt-3, c-KIT, and RET. Sorafenib has broad spectrum in vivo activity against a number of tumor types, and has proven clinical efficacy in patients with metastatic renal cell carcinoma [10]. This activity, taken together with the evidence linking progression of prostate cancer and activation of growth factor signaling pathways through raf and angiogenesis through VEGFR, provided a rationale to study the antitumor activity of sorafenib in patients with castration-resistant prostate cancer.
Annals of Oncology
original article
Annals of Oncology
results patient characteristics Twenty-eight patients were enrolled from July 2004 to December 2005, with the first stage accruing from June 2004 to November 2004 and the second stage from August to December 2005. All 28 patients were assessable for adverse events, 27 were assessable for PSA response, and 8 had evaluable measurable disease. Median age was 67 years (range 49–84 years); no patients had received prior chemotherapy, and 26 patients had evidence of local and/or metastatic disease with two patients having only rising PSA as evidence of disease. Patient baseline characteristics are listed in Table 1.
Table 1. Patient characteristics Characteristics Age Time from diagnosis Gleason score 6 or 7 8 or 9 Unknown Performance status 0 1 Prior therapy Hormonal therapy Radiotherapy Chemotherapy Other Albumin (g/l)
Number of patients (N = 28)
adverse events In general, protocol therapy was well tolerated with adverse events attributed to sorafenib being similar to what have been previously described [10]. The majority of missed or reduced doses were due to grade 2 or 3 hand–foot syndrome, rash, and/ or fatigue. The most common adverse events included fatigue (54% of patients), skin rash (50%), hand–foot syndrome (39%), anorexia (36%), diarrhea (32%), and heartburn (32%). These were grade 1–2 in severity with the exception of one patient experiencing grade 3 fatigue and two with grade 3 hand–foot syndrome. One patient had grade 3 neutropenia on study, and an additional patient had grade 3 neutropenia 28 days after discontinuing sorafenib and receiving radiation. Laboratory adverse events have been mild. In patients with
Median (range) 67 (49–84) years 67.2 (19–171) months
Table 2. Adverse events attributed to be at least possibly related to protocol therapy, occurring in >10% of patients Adverse event
10 11 7 19 9 28 18 0 1 39 (29–47) 2 26 133 28 0 22 13 3 3 2 2 4 2 16 4 5 1
Grade
Number of patients—worst by grade (N = 28) 1 2
Hand–foot syndrome Increased AST Granulocytopenia Fatigue Lymphopenia Anemia Leukocytopenia Hypertension Hypoalbuminemia Skin rash Increased bilirubin Platelets Taste alteration Increased ALT Dry skin Mucositis Abdominal pain Anorexia Heartburn Pruritis Vomiting Sensory neuropathy Fever Diarrhea Constipation Nausea Creatinine Alopecia Throat pain
4 7 2 9 5 15 5 1 2 10 3 8 5 5 4 4 4 9 8 5 4 4 2 9 7 6 5 5 3
5 3 0 5 5 2 1 1 5 4 4 2 2 2 2 2 2 1 1 1 1 1 1
3 2 2 2 1 1 1 1 1
AST, aspartate transaminase; ALT, alanine transaminase.
doi:10.1093/annonc/mdm554 | 3
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treatments administered Median number of cycles delivered was two (range 1–8). Fifteen patients discontinued protocol therapy because of rising PSA, five because of progressive disease, two patients refused further treatment, four for other reasons, and one patient discontinued
therapy because of hematologic adverse events with grade 3 anemia and grade 2 thrombocytopenia. Fifty-seven percent of patients received ‡90% of planned dose intensity. Nineteen patients missed at least one dose with 75% of missed doses being due to an adverse event, four had dose delays, eight had dose reductions, and one patient had an increase in dose after an initial dose reduction for hand–foot syndrome.
original article
Annals of Oncology
normal baseline chemistries, these have been grade 1–2 in severity with the exception of one patient experiencing grade 3 elevated AST. Table 2 lists adverse events considered at least possibly related to protocol therapy.
Percentage Change in PSA from Baseline
Figure 1. Plot of greatest percentage change in prostate-specific antigen (PSA) of individual patients while on protocol therapy for all patients.
progression-free survival and OS. Median time to PSA progression was 2.1 months (95% CI 1.8–6.4) (Figure 3) and time to treatment failure was 1.8 months (95% CI 1.7–2.8). OS was 12.25 months (95% CI 6.7–16.46). PSA declines after discontinuation of sorafenib. There were 26 patients with PSA data available for analysis of PSA change after discontinuation of protocol therapy. Sixteen patients had not received any immediate treatment after discontinuing sorafenib and 10 of these patients had a PSA decline of 7%–52% (as compared with the last PSA while on sorafenib therapy). Ten patients received immediate therapy after discontinuing sorafenib: four patients received palliative radiation, three received corticosteroids 6 ketoconazole, two received treatment with chemotherapy (mitoxantrone and docetaxel) and one was given a nonsteroidal antiandrogen. Of these 10 patients, 8 had a PSA decline of 14%–91%.
correlative studies BRAF mutation. PCR amplification was successful in 13 of 26 cases for BRAF exon 11 and 14 of 26 cases for BRAF exon 15. DHPLC analysis revealed a single case in which five unclassified Time to PSA Proression
800
100
700 80
600 500
60
400
% 40
300 200
20
100 0
0 0
10
20
30
40
Weeks Figure 2. Plot of percentage change in prostate-specific antigen (PSA) of individual patients over time while on protocol therapy.
4 | Chi et al.
0.0 At Risk: 27
2.0 14
4.0 6
6.0 1
Time (Months) Figure 3. Time to prostate-specific antigen (PSA) progression.
8.0 0
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antitumor activity PSA declines. In the first stage of accrual for the study, one patient experienced a post-treatment PSA decline of ‡50% that was confirmed 4 weeks later. The baseline PSA in this patient was 10 000 lg/l and decreased to a nadir level of 1643 lg/l, with a time to PSA progression of 2.82 months. No patients accrued in the second stage had a post-treatment PSA decline of ‡50%. The PSA response rate among all assessable patients was 3.6% (95% CI 0.1% to 18.3%). Five patients experienced PSA declines of <50%: two had declines of 25%–49% and three had declines of <25%. The greatest percentage change in PSA while on protocol therapy for all patients is depicted in Figure 1. Figure 2 plots change in PSA for individual patients over time while on protocol therapy. Several patients had an initial increase in PSA which was followed by an apparent decline or stabilization, however, protocol-mandated procedures required discontinuation of these patients from sorafenib therapy because of that initial PSA rise.
measurable disease responses. Twelve patients were enrolled with measurable disease. Five of the patients had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) as their best objective response, three had progressive disease, and four were inevaluable [response rate = 0% (95% CI 0% to 31.2%)]. Sixteen patients had nonmeasurable disease only; three had a best response of progression (increasing lesions on bone scan) while the other 13 were inevaluable by RECIST criteria response or progression. For patients who went off protocol therapy after meeting PSA progression criteria, eight had measurable disease and two of these patients had stable disease and four had progressive disease by RECIST criteria at the time of sorafenib discontinuation. Of the other 13 patients, 5 had nonmeasurable disease and 5 had met RECIST criteria for disease progression at the time of sorafenib discontinuation.
original article
Annals of Oncology
variants were identified in exon 15, none of which have been previously reported to activate BRAF. This patient had an increasing PSA as best PSA response. immunohistochemistry. Twenty-five patients had sufficient tissues for analysis (Figure 4). There were no statistically significant correlations between immunohistochemistry scores for EGFR, IGF1R, ERK, phosphorylated-ERK, and VEGFR-2 and baseline clinical factors (age, performance status, Gleason score, time from diagnosis of disease to registration of the study, and liver metastases) or PSA changes during or after protocol therapy with sorafenib.
discussion
100
Percentage of Cases
90 80 70 60 50 40 30 20 10 0 0 1 2 VEGFR2
0 1 2 ERK
0 1 2 P-ERK
0 2 1 IGF1R
0 1 2 EGFR
Immunohistochemistry Scoring Figure 4. Immunohistochemistry scoring in primary tumor biopsies for vascular endothelial growth factor receptor-2 (VEGFR-2), ERK, phosphorylated-ERK, insulin-like growth factor 1 receptor (IGF1R), and epidermal growth factor receptor (EGFR).
funding National Cancer Institute of Canada, Canadian Cancer Society.
acknowledgements Sorafenib was provided by the National Cancer Institute Cancer Therapy Evaluation Program.
doi:10.1093/annonc/mdm554 | 5
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Progression of prostate cancer to androgen independence has been associated with a number of processes including activation of growth factor signaling pathways [3]. Several agents targeting these pathways have been tested but despite encouraging preclinical data, clinical results have been disappointing [16, 17]. In this study, we evaluated the multitargeted kinase inhibitor sorafenib. Using accepted criteria for reporting PSA declines on clinical trials [12], only limited activity was seen, with one notable case of a 90% decrease in PSA and five patients with lesser decreases. Closer inspection of the data indicate that some patients had an initially rising PSA while on therapy which then appeared to start stabilizing (Figure 2); however, protocol-mandated discontinuation rules required the patients to come off therapy on the basis of the initial PSA rise alone. In addition, 62% of patients were found to have a decreasing PSA after discontinuing protocol therapy with sorafenib therapy despite receiving no additional therapy. Even in those patients who did receive some sort of immediate postprotocol therapy, 80% had post-treatment PSA declines, which could be considered an unexpectedly high response rate, given the nature of the treatments received. These results delineate a number of challenges when assessing activity of targeted therapies in patients with castrationresistant prostate cancer. The first is the use and reliance on PSA as the only quantifiable measure of response and treatment failure. Although an important and useful tumor marker,
clinical benefit is not entirely reflected by PSA changes alone [18]. The observed PSA declines after withdrawal of sorafenib therapy could indicate an isolated effect on PSA production or secretion separate from sorafenib’s antitumor activity. This effect may also be transient given the initial rise in PSA seen in several patients followed by an apparent stabilization or inflection. An effect of sorafenib on PSA production/secretion is further supported by recently presented data from a study of sorafenib in patients with castration-resistant prostate cancer which included patients who had previously received chemotherapy [19]. No PSA responses were observed in that study, but cases of metastatic bone disease responding independently of PSA were noted. Preclinical studies were also presented which demonstrated an effect of sorafenib on PSA production/secretion that was separate of its cytotoxic effect [19]. Additionally, attenuation of Ras signaling has been shown to restore androgen sensitivity in hormone-refractory C4-2 prostate cancer cells [20], and thus the sorafenib associated increase in PSA could relate to increased activation of androgen receptor through inhibition of MAPK signaling pathways. This latter hypothesis raises a further therapeutic strategy that could be explored of combining growth factor signal targeting and androgen receptor inhibition. Another obstacle to study targeted therapies in patients with prostate cancer is the lack of representative malignant tissue available for correlative studies. Castration-resistant disease presents predominantly as bone metastases and is thus not amenable to convenient sampling [21]. Extrapolating expression of a particular biomarker from initial tumor biopsies of androgen-dependent disease to the castrationresistant state is potentially flawed because of the well-described gene expression shifts that occur with the emergence of androgen independence [22]. In this study, we attempted to evaluate primary tissues and correlate with baseline factors and outcomes and no associations were apparent. This could perhaps be expected given the previous caveats, small number of subjects, and limited PSA responses. One patient was identified as having five variants within exon 15 of BRAF, none of which have been previously associated with activation of BRAF, and in this case there was no association with a clinical response. The fact that PSA response may not even be a relevant end point for sorafenib further weakens this analysis. In conclusion, for patients with castration-resistant prostate cancer, sorafenib induces minimal PSA responses as defined by accepted criteria. The limitations of PSA as the primary indicator of response and progression in this setting, however, need to be considered. Additional trials are under way evaluating sorafenib in patients with castration-resistant disease, including combinations with the nonsteroidal antiandrogen bicalutamide and mitoxantrone.
original article references
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Annals of Oncology