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Life after failure of traditional androgen deprivation therapy
Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
Article
Life after failure of traditional androgen deprivation therapy Paul Schellhammer, M.D.* Eastern Virginia Medical School, Virginia Beach, VA 23464, USA Received 17 August 2011; received in revised form 17 January 2012; accepted 19 January 2012
Abstract Castrate resistant prostate cancer is a disease state which, counterintuitively, can be successfully treated with additional therapy directed at inhibition of androgen synthesis and/or interfering with the activity of the androgen receptor. Novel androgen biosynthesis inhibitors and antiandrogens are now being tested in large phase 3 clinical trials to clarify their role in the treatment of men who have failed traditional medical castration, with or without currently available nonsteroidal antiandrogens. A renewed interest in studying parenteral delivery of estrogens may provide evidence to revisit the initial medical therapy for advancing prostate cancer. © 2012 Elsevier Inc. All rights reserved. Keywords: Castrate resistant prostate cancer; Androgen biosynthesis inhibitors; Anti-androgens; Estrogen
Introduction Against the background of dramatically improving prostate cancer (CaP)-specific survival rates, rising from 67% to 99% between 1974 and 2000, healthcare economists and physicians not familiar with the natural history of CaP might question the urologists’ concern about morbidity and mortality because of advancing disease. Early detection and the resultant lead time bias have made CaP 5-year survival statistics relatively meaningless for predicting subsequent outcomes. Follow-up through 10, and even 15 years is necessary to appreciate the lethal phenotype of CaP that will claim the life of approximately 32,000 men in 2011. Advancing CaP and androgen deprivation Advancing CaP is a dynamic process. In years past, it was defined by the finding of bulky disease on digital rectal examination, or imaging studies demonstrating adenopathy or bone metastases, but these are now not the usual criteria. “Where have all the signs and symptoms gone?” was the subject of a recent text chapter in Comprehensive Textbook of Genitourinary Oncology, 3rd edition [1]. While there are no absolute criteria to identify this disease state, a combi-
Disclosure/Conflict of Interest Statement: P. Schellhammer is an advisory board member and on the Speakers Bureau for Dendreon Corporation. He also owns stock in Medivation, Inc. * Corresponding author. Tel.: 757-452-3463; fax: 757-627-3573. E-mail address: [email protected] (P. Schellhammer). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2012.01.009
nation of risk factors, which include absolute serum prostatic specific antigen (PSA) levels, PSA kinetics (rapid doubling time and velocity), especially if serum testosterone is at castration levels, and/or disease progression by imaging studies (bone scan, CT scan, MRI), are important criteria for identifying advancing disease. Virtually all patients with advancing disease state will receive androgen deprivation, either by luteinizing hormone-releasing hormone (LHRH) agonist monotherapy or an LHRH agonist in combination with a nonsteroidal antiandrogen. Combined androgen blockade was a strategy introduced more than 20 years ago to maximize androgen deprivation by addressing the possibility of adrenal androgen production and the possibility of incomplete gonadal axis suppression, and did indeed demonstrate a 5-year 2.9% survival advantage vs. monotherapy when either nilutamide or flutamide was employed [2]. A retrospective analysis and a prospective combined androgen blockade trial with bicalutamide for patients with T3 or M1 disease have demonstrated an overall survival advantage for the combination compared with LHRH agonist monotherapy [3,4]. An improved understanding of the androgen receptor and its continued activity, even at low levels of androgen, has led to the development of agents to approach more “complete” androgen blockade with more profound and durable response. A critical question to be resolved is the testosterone cutpoint, which defines optimal therapy. Unfortunately, progress towards this end is impeded by nonstandardized methodology and limited sensitivity of testosterone assays [5].
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
Parenthetically, as we proceed towards the objective of androgen “annihilation,” the resulting adverse consequences will need even greater attention. Bone health has been recognized as a victim of long-term androgen deprivation and, more recently, cardiovascular and metabolic health as well. The American Heart Association, American Urologic Association, and the American Cancer Society have recently issued guidelines with which every physician prescribing androgen deprivation therapy should have familiarity [6]. Estrogen plays a well-defined role in bone health and sexual function, and may play a role in cognitive function and lipid physiology. In the male, estrogen is derived from aromatization of testosterone. It follows that further lowering of the testosterone nadir will be accompanied by increasing estrogen deficiency and, logically, more potential for adverse events. The impact of lower testosterone nadir on quality-of-life when used early in the course of disease, a situation dramatically different from use as currently tested in trials of chemo-naive or post-chemometastatic castrate-resistant CaP, may be found to be problematic or even prohibitive. The role of estrogen supplementation to offset marked estrogen deficiency will become a subject for future consideration. Definitions of disease state PSA or imaging progression while the patient is receiving LHRH analogue monotherapy has long been labeled hormone refractory disease. This is obviously inaccurate, since subsequent hormonal interventions are now available to induce disease regression. Another label has been androgen-independent disease, which is also inaccurate as the androgen receptor remains, as discussed above, quite active. The current label for this disease state is castration-resistant. This label depends on the definition of a castrate serum testosterone. Should it be the traditional Food and Drug Administration (FDA) recognized cutpoint of ⬍50 ng/dl, or the lower than 20 ng/dl achieved by surgical castration, or should it rely on more sensitive assays that can measure testosterone to ⬍1 ng/dl; finally, should the castrate state consider tissue and tumor, as well as serum androgen levels? Androgen levels of CaP tissue had been shown to be comparable to or only slightly less than that of benign prostate tissue, and expression of steroidogenic enzyme transcripts that would facilitate the conversion of cholesterol to androgens are found in higher concentration in metastatic CaP samples vs. tissue from the primary cancer or benign prostate tissue [7,8]. This information clearly defines a paracrine/autocrine phase of CaP that has implications beyond the historical/traditional endocrine phase defined by serum testosterone level. There is increasing clinical experience that progression of disease to the castration resistant state can be delayed and overall survival prolonged by achieving and maintaining lower testosterone nadirs [9,10]. While it has not been the routine practice of urologists to obtain periodic testosterone
S11
monitoring along with PSA determinations after the institution of an LHRH agonist, this will be necessary to clarify/ document optimal testosterone nadir levels. Furthermore, testosterone monitoring is recommended in the FDA labeling of the LHRH agonists. Androgen biosynthesis inhibitor (ABI) The androgen receptor is active in the “castrate state” based on the number of possible mechanisms, which include amplification, hypersensitivity, mutation, and or ligand-independent activation. There are a number of strategies in development to suppress androgen receptor activation by more effective receptor blockade and/or more effective reduction of the androgen ligand. Ketoconazole is a currently available drug that can accomplish the goal of ligand reduction. Ketoconazole can be considered a forerunner of the androgen biosynthesis inhibitors. It is a general, nonspecific inhibitor of the CYP enzyme family (17␣-hydroxylase 0.17,20 lyase) that converts cholesterol to androgens. It carries the disadvantage of interfering with the metabolic degradation of other pharmacologic agents (statins, erythromycin, calcium channel blockers, selective serotonin reuptake inhibitors (SSRIs), and acetaminophen.) Therefore, it is necessary to take a careful medication history and consult with primary care physician for medication changes before prescribing. Abiraterone, orally administered, is a 17␣-hydroxylase 17,20 lyase irreversible enzyme inhibitor, which is more specific and more potent than ketoconazole. In addition to its activity in testicular and adrenal tissue, it is also active in blocking androgen production in tumor tissue. In phase 2 studies, abiraterone demonstrated significant PSA declines (⬎50% in two-thirds of patients and ⬎90% in 20% of patients) along with objective responses [11–13]. Patients who had been treated previously with ketoconazole also demonstrated a response. Abiraterone is currently being tested in 2 large randomized controlled trials (RCTs); one enrolling patients with castrate resistant CaP post-docetaxel and the other pre-docetaxel, both trials have met accrual, and one has been published [14]. This large phase 3 trial enrolled men with metastatic castrate resistant CaP who had failed docetaxel chemotherapy, randomizing them to abiraterone 1 g daily plus prednisone 5 mg bid vs. placebo plus prednisone with an endpoint of overall survival. That these men were a cohort with advancing disease who had virtually exhausted all avenues of therapy is illustrated by the fact that 28% had been treated with at least 2 prior chemotherapies and 10%–15% demonstrated liver and lung metastases. The treatment arm demonstrated a 3.9month survival benefit with a hazard ratio of 0.646 and a P value of ⬍0.001. Abiraterone is quite well tolerated. Side effects include hypokalemia, fluid retention, and hypertension, a consequence of downstream excess aldosterone. The administration of prednisone counters the feedback loop that produces excess aldosterone, but periodic blood pres-
S12
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
sure, weight, and electrolyte monitoring are necessary. The second trial is using the same protocol but enrolling patients with castrate-resistant metastatic CaP before docetaxel exposure. Another androgen biosynthesis inhibitor, a 17,20 lyase inhibitor, TAK 700 (orteronel) is undergoing a similar trial development pathway. The strategy of further depressing testosterone to effect better cancer control has been questioned in light of the results of intermittent therapy trials that aimed at periodic testosterone restoration and which have thus far, in the context of clinical trials, shown little difference in outcomes compared with continuous androgen deprivation maintaining a castrate state (by current definition less than 50 ng/dl) [15]. What is unknown is the benefit that would accrue from lower testosterone nadirs during the on cycle. Morote showed that consistent testosterone ⬍20 ng/dl using continuous androgen deprivation delayed the onset of castrate resistant disease [9]. Likewise, a lower testosterone nadir during the treatment cycle of an intermittent protocol may affect more durable control of PSA, prolong the time off cycle, and the time to the castrate resistant state (Fig. 1). Antiandrogens MDV3100 promises to be a more effective androgen receptor blocker than the nonsteroidal antiandrogens currently available. This molecule not only has a greater affinity than bicalutamide for the androgen receptor, but also impairs nuclear translocation and DNA-binding as well as disabling nuclear coactivators. It, therefore, provides a multipronged attack against its target. Phase 2 trial data demonstrated a ⬎50% reduction in PSA in more than 50% of the population treated, reversal of unfavorable circulating tumor cell counts, and was well tolerated [16]. Phase 3 trials, paralleling eligibility criteria and endpoints of the abiraterone trials are in process. The Affirm trial has enrolled approximately 1,200 patients with castrate-resistant CaP post-docetaxel chemotherapy comparing MDV3100, 160 mg, to a control arm (placebo or prednisone) with a survival endpoint. An interim analysis of this trial demonstrated a highly statistically significant survival benefit for the MDV3100 arm. The Data Monitoring Committee recommended trial closure and MDV3100 for control arm subjects in view of this survival benefit. The trial details have not, as yet, been presented or published. The Prevail trial, testing MDV3100 among patients with chemotherapynaive, metastatic castrate-resistant CaP, is currently accruing. A randomized phase 2 trial (Terrain) is enrolling patients with metastatic castration-resistant CaP receiving LHRH agonist monotherapy to compare the addition of bicalutamide 50 mg vs. MDV3100, 160 mg, with a disease progression endpoint. As the androgen biosynthesis inhibitors and the new antiandrogens enter clinical practice, the question of sequence or combination of these therapies will be addressed by future clinical trials. Since these agents have differing
Fig. 1. PSA and testosterone levels during the on and off cycle for a hypothetical patient on intermittent androgen deprivation. Top graph shows testosterone nadir to be 30 – 40 ng/dL with castrate-resistant disease developing at 36 months. Bottom graph shows testosterone nadir to be below 10 ng/dL with more durable off cycle PSA suppression without evidence of castration resistant disease at 36 months. Whether lower testosterone nadir on cycle, as illustrated, will increase duration of off cycle, warrants investigation. (Color version of figure is available online.)
mechanisms of action, namely androgen biosynthesis inhibitor for reduction of the androgen ligand and more effective blockade of the androgen receptor target by MDV3100, a combination of the two may indeed lead to androgen annihilation, which may incapacitate CaP to a degree that that has thus far not been possible. Furthermore, the androgen receptor is now recognized as an integral factor in the activity not only of the prostate epithelial cell that has metastasized to bone but also as a component of the biology of the osseous stromal microenvironments. Therefore, the ABIs and antiandrogens effect a dual action in modulating the “vicious cycle” that occurs when prostate metastasizes to bone. Also targeting the microenvironment are zoledronic acid, an osteoclast inhibitor, denosumab, a monoclonal antibody against the RANK L–RANK receptor pathway that drives osteoblast/osteoclast activity, and alpha radin, a alpha emitting radio-pharmaceutical with palliative and survival benefits (unpublished data). These agents will enter the foray to blunt the morbidity and mortality of the castrate-resistant disease state.
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
Estrogens redux Oral estrogens to suppress testosterone, the most effective strategy for treatment of an epithelial cancer, was introduced in 1941 by the Nobel laureate Dr. Charles Huggins. The large Veteran’s Association Cooperative Group trials compared the benefit and side effects of diethylstilbestrol to orchiectomy [17]. While oral estrogen demonstrated a superior cancer-specific survival, the associated cardiovascular morbidity and mortality negated this survival benefit. Because of this, the use of oral estrogen therapy was traditionally withheld until the appearance of symptoms from advancing disease. The introduction of LHRH agonist therapy provided a means of medically-induced androgensuppression-absent cardiovascular and thromboembolic side effects. However, the superiority of estrogen to orchiectomy in extending cancer-specific survival due to a mechanism of action that included both testosterone suppression and direct cellular cytotoxicity effect prompted the investigation of alternative estrogen delivery systems [18]. The adverse effects of oral estrogen can be circumvented by transdermal delivery. By avoiding the enterohepatic circulation and first pass through the liver, the cardiovascular and thromboembolic events associated with oral estrogen can be markedly reduced [18]. Parenteral estrogen presents a win-win situation; a win in the arena of more effective antitumor response, and a win by reducing the skeletal related consequences of the hot flashes and the adverse impact on sexual function secondary to estrogen deprivation [19]. The transdermal estrogen delivery strategy is being subjected to level 1 evidence testing through a large RCT being conducted in the UK. The patch trial eligibility criteria, protocol, and endpoints are illustrated in the Fig. 2. Challenges Sixty-three years elapsed between 1941, when Charles Huggins introduced androgen deprivation as effective ther-
Estrogen Patch Trial United Kingdom Newly diagnosed or relapsing patients with locally advanced or metastatic prostate cancer
2200 Control Arm
Randomization
LHRH analogues given as per local practice indefinitely
Investigational Arm
Transcutaneous estrogen patches indefinitely
Primary endpoint: Overall Survival Secondary Endpoint: Castrate T, PSA failure, Toxicity, QOL, Prostate Prostate Specific Mortality
Fig. 2. United kingdom estrogen patch trial. (Color version of figure is available online.)
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apy for metastatic CaP and 2004, when docetaxel was FDA approved for castrate resistant metastatic CaP. Between 2004 and 2010, a bright line has separated urologic care and medical oncology care of advancing CaP; the urologists using androgen deprivation and no more, the medical oncologist using chemotherapy, and no less. The year 2010 has seen the approval of sipuleucel-T immunotherapy and cabazitaxel second line chemotherapy, and on the immediate horizon are abiraterone for more effective testosterone/ androgen suppression and the antiandrogen MDV3100 for more effective blockade of the androgen receptor. These agents have different class effect, attack the cancer through different mechanisms of action, and will either sequentially or in combination have a role in therapy. The challenge to urologists and medical oncologists will be to take down the bright line and together construct and accrue trials that clarify whether the best use of these agents will be sequential and/or in combination delivery, while addressing the daunting issues of quality-of-life and cost. This interdisciplinary mixing and cooperation will translate into better outcomes for patients with advancing CaP.
References [1] Davis JW, Schellhammer PF. Clinical signs and symptoms of prostate cancer, In: Comprehensive textbook of genitourinary oncology, 3rd ed. Vogelzang NJ, Scardino PT, Shipley WU, Debruyne F, Linehan WM. Lippincott Williams & Wilkins, 2006. [2] Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: An overview of the randomized trials. Lancet 2000;355:1491– 8. [3] Klotz L, Schellhammer P, Carroll K. A reassessment of the role of combined androgen blockade for advanced prostate cancer. BJU Int 2004;93:1177– 82. [4] Akaza H, Hinotsu S, Usami M, et al. Combined androgen blockade with bicalutamide for advanced prostate cancer: Long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer 2009;115:3437– 45. [5] Rosner W, Vesper H. Endocrine Society, American Association for Clinical Chemistry, American Association of Clinical Endocrinologists, Androgen Excess/PCOS Society, American Society for Bone and Mineral Research, American Society for Reproductive Medicine, American Urological Association, et al. Association of Public Health Laboratories; Endocrine Society; Laboratory Corporation of America; North American Menopause Society; Pediatric Endocrine Society. Toward excellence in testosterone testing: A consensus statement. J Clin Endocrinol Metab 2010;95:4542– 8. [6] Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: A science advisory from the American Heart Association, American Cancer Society and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010;60:194 –201. [7] Mohler JL, Gregory CW, Ford OH III, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10:440 – 8. [8] Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res 2008;68: 4447–54. [9] Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 2007;178:1290 –5.
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[10] Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: Prognostic significance? BJU Int 2010;105:648 –51. [11] Attard G, Reid AH, de Bono JS. Abiraterone acetate is well tolerated without concomitant use of corticosteroids. J Clin Oncol 2010;28:e560–1. [12] Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxeltreated, castration-resistant prostate cancer. J Clin Oncol 2010;28:1496–501. [13] Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489–95. [14] de Bono JS, Logothetis CJ, Molina A, et al. COU-AA-301 investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005. [15] Klotz L. A phase III randomized Trial Comparing Intermittent Versus Continuous Androgen Suppression for Patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/
[16]
[17]
[18]
[19]
CTSU JPR.7/UK intercontinental trial CRUKE/01/013. ASCO Genitourinary Cancers Symposium. Abstract 43. Presented 2011. J Clin Oncol 2011;29(Suppl 7): Abstract 3. Scher HI, Beer TM, Higano CS, et al. Phase I–II study of MDV3100 in castration-resistant prostate cancer (CRPC). Proceedings of the ASCO Genitourin Cancers Symposium. 2009; Abstract 151. Byar DP, Corle DK. Hormone therapy for prostate cancer: Results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 1988;7:165–70. Ockrim JL, Lalani EN, Banks LM, et al. Transdermal estradiol improve bone density when used as single agent therapy for prostate cancer. J Urol 2004;172:203–7. Wibowo E, Schellhammer P, Wassersug RJ. Role of estrogen in normal male function: Clinical implications for patients with prostate cancer on androgen deprivation therapy. J Urol 2011;185: 17–23.
Article
Life after failure of traditional androgen deprivation therapy Paul Schellhammer, M.D.* Eastern Virginia Medical School, Virginia Beach, VA 23464, USA Received 17 August 2011; received in revised form 17 January 2012; accepted 19 January 2012
Abstract Castrate resistant prostate cancer is a disease state which, counterintuitively, can be successfully treated with additional therapy directed at inhibition of androgen synthesis and/or interfering with the activity of the androgen receptor. Novel androgen biosynthesis inhibitors and antiandrogens are now being tested in large phase 3 clinical trials to clarify their role in the treatment of men who have failed traditional medical castration, with or without currently available nonsteroidal antiandrogens. A renewed interest in studying parenteral delivery of estrogens may provide evidence to revisit the initial medical therapy for advancing prostate cancer. © 2012 Elsevier Inc. All rights reserved. Keywords: Castrate resistant prostate cancer; Androgen biosynthesis inhibitors; Anti-androgens; Estrogen
Introduction Against the background of dramatically improving prostate cancer (CaP)-specific survival rates, rising from 67% to 99% between 1974 and 2000, healthcare economists and physicians not familiar with the natural history of CaP might question the urologists’ concern about morbidity and mortality because of advancing disease. Early detection and the resultant lead time bias have made CaP 5-year survival statistics relatively meaningless for predicting subsequent outcomes. Follow-up through 10, and even 15 years is necessary to appreciate the lethal phenotype of CaP that will claim the life of approximately 32,000 men in 2011. Advancing CaP and androgen deprivation Advancing CaP is a dynamic process. In years past, it was defined by the finding of bulky disease on digital rectal examination, or imaging studies demonstrating adenopathy or bone metastases, but these are now not the usual criteria. “Where have all the signs and symptoms gone?” was the subject of a recent text chapter in Comprehensive Textbook of Genitourinary Oncology, 3rd edition [1]. While there are no absolute criteria to identify this disease state, a combi-
Disclosure/Conflict of Interest Statement: P. Schellhammer is an advisory board member and on the Speakers Bureau for Dendreon Corporation. He also owns stock in Medivation, Inc. * Corresponding author. Tel.: 757-452-3463; fax: 757-627-3573. E-mail address: [email protected] (P. Schellhammer). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2012.01.009
nation of risk factors, which include absolute serum prostatic specific antigen (PSA) levels, PSA kinetics (rapid doubling time and velocity), especially if serum testosterone is at castration levels, and/or disease progression by imaging studies (bone scan, CT scan, MRI), are important criteria for identifying advancing disease. Virtually all patients with advancing disease state will receive androgen deprivation, either by luteinizing hormone-releasing hormone (LHRH) agonist monotherapy or an LHRH agonist in combination with a nonsteroidal antiandrogen. Combined androgen blockade was a strategy introduced more than 20 years ago to maximize androgen deprivation by addressing the possibility of adrenal androgen production and the possibility of incomplete gonadal axis suppression, and did indeed demonstrate a 5-year 2.9% survival advantage vs. monotherapy when either nilutamide or flutamide was employed [2]. A retrospective analysis and a prospective combined androgen blockade trial with bicalutamide for patients with T3 or M1 disease have demonstrated an overall survival advantage for the combination compared with LHRH agonist monotherapy [3,4]. An improved understanding of the androgen receptor and its continued activity, even at low levels of androgen, has led to the development of agents to approach more “complete” androgen blockade with more profound and durable response. A critical question to be resolved is the testosterone cutpoint, which defines optimal therapy. Unfortunately, progress towards this end is impeded by nonstandardized methodology and limited sensitivity of testosterone assays [5].
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
Parenthetically, as we proceed towards the objective of androgen “annihilation,” the resulting adverse consequences will need even greater attention. Bone health has been recognized as a victim of long-term androgen deprivation and, more recently, cardiovascular and metabolic health as well. The American Heart Association, American Urologic Association, and the American Cancer Society have recently issued guidelines with which every physician prescribing androgen deprivation therapy should have familiarity [6]. Estrogen plays a well-defined role in bone health and sexual function, and may play a role in cognitive function and lipid physiology. In the male, estrogen is derived from aromatization of testosterone. It follows that further lowering of the testosterone nadir will be accompanied by increasing estrogen deficiency and, logically, more potential for adverse events. The impact of lower testosterone nadir on quality-of-life when used early in the course of disease, a situation dramatically different from use as currently tested in trials of chemo-naive or post-chemometastatic castrate-resistant CaP, may be found to be problematic or even prohibitive. The role of estrogen supplementation to offset marked estrogen deficiency will become a subject for future consideration. Definitions of disease state PSA or imaging progression while the patient is receiving LHRH analogue monotherapy has long been labeled hormone refractory disease. This is obviously inaccurate, since subsequent hormonal interventions are now available to induce disease regression. Another label has been androgen-independent disease, which is also inaccurate as the androgen receptor remains, as discussed above, quite active. The current label for this disease state is castration-resistant. This label depends on the definition of a castrate serum testosterone. Should it be the traditional Food and Drug Administration (FDA) recognized cutpoint of ⬍50 ng/dl, or the lower than 20 ng/dl achieved by surgical castration, or should it rely on more sensitive assays that can measure testosterone to ⬍1 ng/dl; finally, should the castrate state consider tissue and tumor, as well as serum androgen levels? Androgen levels of CaP tissue had been shown to be comparable to or only slightly less than that of benign prostate tissue, and expression of steroidogenic enzyme transcripts that would facilitate the conversion of cholesterol to androgens are found in higher concentration in metastatic CaP samples vs. tissue from the primary cancer or benign prostate tissue [7,8]. This information clearly defines a paracrine/autocrine phase of CaP that has implications beyond the historical/traditional endocrine phase defined by serum testosterone level. There is increasing clinical experience that progression of disease to the castration resistant state can be delayed and overall survival prolonged by achieving and maintaining lower testosterone nadirs [9,10]. While it has not been the routine practice of urologists to obtain periodic testosterone
S11
monitoring along with PSA determinations after the institution of an LHRH agonist, this will be necessary to clarify/ document optimal testosterone nadir levels. Furthermore, testosterone monitoring is recommended in the FDA labeling of the LHRH agonists. Androgen biosynthesis inhibitor (ABI) The androgen receptor is active in the “castrate state” based on the number of possible mechanisms, which include amplification, hypersensitivity, mutation, and or ligand-independent activation. There are a number of strategies in development to suppress androgen receptor activation by more effective receptor blockade and/or more effective reduction of the androgen ligand. Ketoconazole is a currently available drug that can accomplish the goal of ligand reduction. Ketoconazole can be considered a forerunner of the androgen biosynthesis inhibitors. It is a general, nonspecific inhibitor of the CYP enzyme family (17␣-hydroxylase 0.17,20 lyase) that converts cholesterol to androgens. It carries the disadvantage of interfering with the metabolic degradation of other pharmacologic agents (statins, erythromycin, calcium channel blockers, selective serotonin reuptake inhibitors (SSRIs), and acetaminophen.) Therefore, it is necessary to take a careful medication history and consult with primary care physician for medication changes before prescribing. Abiraterone, orally administered, is a 17␣-hydroxylase 17,20 lyase irreversible enzyme inhibitor, which is more specific and more potent than ketoconazole. In addition to its activity in testicular and adrenal tissue, it is also active in blocking androgen production in tumor tissue. In phase 2 studies, abiraterone demonstrated significant PSA declines (⬎50% in two-thirds of patients and ⬎90% in 20% of patients) along with objective responses [11–13]. Patients who had been treated previously with ketoconazole also demonstrated a response. Abiraterone is currently being tested in 2 large randomized controlled trials (RCTs); one enrolling patients with castrate resistant CaP post-docetaxel and the other pre-docetaxel, both trials have met accrual, and one has been published [14]. This large phase 3 trial enrolled men with metastatic castrate resistant CaP who had failed docetaxel chemotherapy, randomizing them to abiraterone 1 g daily plus prednisone 5 mg bid vs. placebo plus prednisone with an endpoint of overall survival. That these men were a cohort with advancing disease who had virtually exhausted all avenues of therapy is illustrated by the fact that 28% had been treated with at least 2 prior chemotherapies and 10%–15% demonstrated liver and lung metastases. The treatment arm demonstrated a 3.9month survival benefit with a hazard ratio of 0.646 and a P value of ⬍0.001. Abiraterone is quite well tolerated. Side effects include hypokalemia, fluid retention, and hypertension, a consequence of downstream excess aldosterone. The administration of prednisone counters the feedback loop that produces excess aldosterone, but periodic blood pres-
S12
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
sure, weight, and electrolyte monitoring are necessary. The second trial is using the same protocol but enrolling patients with castrate-resistant metastatic CaP before docetaxel exposure. Another androgen biosynthesis inhibitor, a 17,20 lyase inhibitor, TAK 700 (orteronel) is undergoing a similar trial development pathway. The strategy of further depressing testosterone to effect better cancer control has been questioned in light of the results of intermittent therapy trials that aimed at periodic testosterone restoration and which have thus far, in the context of clinical trials, shown little difference in outcomes compared with continuous androgen deprivation maintaining a castrate state (by current definition less than 50 ng/dl) [15]. What is unknown is the benefit that would accrue from lower testosterone nadirs during the on cycle. Morote showed that consistent testosterone ⬍20 ng/dl using continuous androgen deprivation delayed the onset of castrate resistant disease [9]. Likewise, a lower testosterone nadir during the treatment cycle of an intermittent protocol may affect more durable control of PSA, prolong the time off cycle, and the time to the castrate resistant state (Fig. 1). Antiandrogens MDV3100 promises to be a more effective androgen receptor blocker than the nonsteroidal antiandrogens currently available. This molecule not only has a greater affinity than bicalutamide for the androgen receptor, but also impairs nuclear translocation and DNA-binding as well as disabling nuclear coactivators. It, therefore, provides a multipronged attack against its target. Phase 2 trial data demonstrated a ⬎50% reduction in PSA in more than 50% of the population treated, reversal of unfavorable circulating tumor cell counts, and was well tolerated [16]. Phase 3 trials, paralleling eligibility criteria and endpoints of the abiraterone trials are in process. The Affirm trial has enrolled approximately 1,200 patients with castrate-resistant CaP post-docetaxel chemotherapy comparing MDV3100, 160 mg, to a control arm (placebo or prednisone) with a survival endpoint. An interim analysis of this trial demonstrated a highly statistically significant survival benefit for the MDV3100 arm. The Data Monitoring Committee recommended trial closure and MDV3100 for control arm subjects in view of this survival benefit. The trial details have not, as yet, been presented or published. The Prevail trial, testing MDV3100 among patients with chemotherapynaive, metastatic castrate-resistant CaP, is currently accruing. A randomized phase 2 trial (Terrain) is enrolling patients with metastatic castration-resistant CaP receiving LHRH agonist monotherapy to compare the addition of bicalutamide 50 mg vs. MDV3100, 160 mg, with a disease progression endpoint. As the androgen biosynthesis inhibitors and the new antiandrogens enter clinical practice, the question of sequence or combination of these therapies will be addressed by future clinical trials. Since these agents have differing
Fig. 1. PSA and testosterone levels during the on and off cycle for a hypothetical patient on intermittent androgen deprivation. Top graph shows testosterone nadir to be 30 – 40 ng/dL with castrate-resistant disease developing at 36 months. Bottom graph shows testosterone nadir to be below 10 ng/dL with more durable off cycle PSA suppression without evidence of castration resistant disease at 36 months. Whether lower testosterone nadir on cycle, as illustrated, will increase duration of off cycle, warrants investigation. (Color version of figure is available online.)
mechanisms of action, namely androgen biosynthesis inhibitor for reduction of the androgen ligand and more effective blockade of the androgen receptor target by MDV3100, a combination of the two may indeed lead to androgen annihilation, which may incapacitate CaP to a degree that that has thus far not been possible. Furthermore, the androgen receptor is now recognized as an integral factor in the activity not only of the prostate epithelial cell that has metastasized to bone but also as a component of the biology of the osseous stromal microenvironments. Therefore, the ABIs and antiandrogens effect a dual action in modulating the “vicious cycle” that occurs when prostate metastasizes to bone. Also targeting the microenvironment are zoledronic acid, an osteoclast inhibitor, denosumab, a monoclonal antibody against the RANK L–RANK receptor pathway that drives osteoblast/osteoclast activity, and alpha radin, a alpha emitting radio-pharmaceutical with palliative and survival benefits (unpublished data). These agents will enter the foray to blunt the morbidity and mortality of the castrate-resistant disease state.
P. Schellhammer / Urologic Oncology: Seminars and Original Investigations 30 (2012) S10 –S14
Estrogens redux Oral estrogens to suppress testosterone, the most effective strategy for treatment of an epithelial cancer, was introduced in 1941 by the Nobel laureate Dr. Charles Huggins. The large Veteran’s Association Cooperative Group trials compared the benefit and side effects of diethylstilbestrol to orchiectomy [17]. While oral estrogen demonstrated a superior cancer-specific survival, the associated cardiovascular morbidity and mortality negated this survival benefit. Because of this, the use of oral estrogen therapy was traditionally withheld until the appearance of symptoms from advancing disease. The introduction of LHRH agonist therapy provided a means of medically-induced androgensuppression-absent cardiovascular and thromboembolic side effects. However, the superiority of estrogen to orchiectomy in extending cancer-specific survival due to a mechanism of action that included both testosterone suppression and direct cellular cytotoxicity effect prompted the investigation of alternative estrogen delivery systems [18]. The adverse effects of oral estrogen can be circumvented by transdermal delivery. By avoiding the enterohepatic circulation and first pass through the liver, the cardiovascular and thromboembolic events associated with oral estrogen can be markedly reduced [18]. Parenteral estrogen presents a win-win situation; a win in the arena of more effective antitumor response, and a win by reducing the skeletal related consequences of the hot flashes and the adverse impact on sexual function secondary to estrogen deprivation [19]. The transdermal estrogen delivery strategy is being subjected to level 1 evidence testing through a large RCT being conducted in the UK. The patch trial eligibility criteria, protocol, and endpoints are illustrated in the Fig. 2. Challenges Sixty-three years elapsed between 1941, when Charles Huggins introduced androgen deprivation as effective ther-
Estrogen Patch Trial United Kingdom Newly diagnosed or relapsing patients with locally advanced or metastatic prostate cancer
2200 Control Arm
Randomization
LHRH analogues given as per local practice indefinitely
Investigational Arm
Transcutaneous estrogen patches indefinitely
Primary endpoint: Overall Survival Secondary Endpoint: Castrate T, PSA failure, Toxicity, QOL, Prostate Prostate Specific Mortality
Fig. 2. United kingdom estrogen patch trial. (Color version of figure is available online.)
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apy for metastatic CaP and 2004, when docetaxel was FDA approved for castrate resistant metastatic CaP. Between 2004 and 2010, a bright line has separated urologic care and medical oncology care of advancing CaP; the urologists using androgen deprivation and no more, the medical oncologist using chemotherapy, and no less. The year 2010 has seen the approval of sipuleucel-T immunotherapy and cabazitaxel second line chemotherapy, and on the immediate horizon are abiraterone for more effective testosterone/ androgen suppression and the antiandrogen MDV3100 for more effective blockade of the androgen receptor. These agents have different class effect, attack the cancer through different mechanisms of action, and will either sequentially or in combination have a role in therapy. The challenge to urologists and medical oncologists will be to take down the bright line and together construct and accrue trials that clarify whether the best use of these agents will be sequential and/or in combination delivery, while addressing the daunting issues of quality-of-life and cost. This interdisciplinary mixing and cooperation will translate into better outcomes for patients with advancing CaP.
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