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5-Alpha Reductase Inhibitors in Prostate Cancer: From Clinical Trials to Clinical Practice
EUROPEAN UROLOGY 63 (2013) 788–791
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the article published on pp. 779–787 of this issue
5-Alpha Reductase Inhibitors in Prostate Cancer: From Clinical Trials to Clinical Practice Behfar Ehdaie a, Karim A. Touijer a,b,* a
Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; b Department of Urology, Weill Medical College of
Cornell University, New York, NY, USA
After a gap of nearly a decade since the introduction of docetaxel, the past 2 years have seen a tremendous expansion of effective new therapeutic agents for castration-resistant prostate cancer (CRPC). These agents have demonstrated advantages in specific outcomes, including longer survival and relief from disease manifestations such as bone pain [1]. Despite questions regarding the proper sequencing of these agents and their integration into an overall treatment plan, the new agents have immediate clinical utility for the management of CRPC. Advances in our understanding of the molecular pathways and genetic factors underlying prostate cancer (PCa) have been primarily responsible for the identification of new targets, new drugs, and new therapeutic strategies. The role of androgen-receptor signaling in particular has received renewed attention. Concurrently, the sharp rise in the incidence of low-risk PCa during the prostate-specific antigen (PSA) era, and the paradigm shift in the management of localized PCa toward active surveillance have led to an evolution of traditional hormonal therapy, specifically 5-a reductase inhibition (5-ARI). The 5-a reductase enzyme is responsible for converting testosterone into dihydrotestosterone, thereby initiating embryologic development of the prostate, growth of prostate glands, and promotion of PCa [2]. In contrast to the newly discovered agents for CRPC, 5-ARIs have not gained wide acceptance in clinical practice despite some evidence of clinical efficacy. Two landmark randomized controlled trials of finasteride and dutasteride demonstrated an advantage in the primary prevention of PCa [3,4]. In secondary prevention, a recent randomized controlled trial in men with very low-risk PCa treated with
active surveillance with or without dutasteride, dutasteride reduced the time to pathologic or therapeutic progression by 38.9%, compared with placebo [5]. Unfortunately, the results of these trials are complicated by controversy regarding end points. The primary prevention studies have been criticized for lack of generalizability because the results were driven largely by mandatory end-of-study prostate biopsies, preferential benefit in preventing lowgrade cancers that do not have an impact on survival, and increased risk of high-grade disease. The secondary prevention study relied on a composite end point for progression (pathologic progression via biopsy or initiation of therapy) and because subjects and investigators were not blind to PSA results, which triggered treatment decisions [5]. In this issue of European Urology, Schro¨der et al. describe the results of a randomized controlled trial evaluating the efficacy of dutasteride in delaying PSA progression in patients with biochemical failure after definitive therapy [6]. Overall, 187 of the 294 men with PSA failure after radical prostatectomy or radiation therapy who were enrolled in the study completed the 24-mo treatment; 107 discontinued treatment prematurely, mainly due to disease progression. The primary end point of the study was time to PSA doubling, and patients who received dutasteride had a significant delay in time to PSA doubling, with a 66.1% relative risk reduction compared with those who received placebo once daily. In addition, dutasteride significantly delayed disease progression compared with placebo, with a relative risk reduction of 59%. The secondary end point of disease progression, however, comprised multiple criteria (ie, number of days between
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2012.11.006. * Corresponding author. Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Tel. +1 646 422 4486; Fax: +1 212 988 0768. E-mail address: [email protected] (K. Touijer). 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 63 (2013) 788–791
the start of treatment and the earliest of any of the following: PSA doubling time 3 mo, or PSA level >20 ng/ml for patients who underwent primary radiotherapy or >10 ng/ml for patients who underwent radical prostatectomy with or without salvage radiotherapy, associated with a 50% increase from baseline PSA level and confirmed in an immediate subsequent PSA measurement, if available; any biopsy-confirmed progression in the clinical T stage; need for additional rescue therapy for PCa; metastatic disease confirmed by bone scan). In fact, fewer than eight patients had measurable progression of disease defined by identification of bone metastases on imaging or biopsy-proven progression. Therefore, the secondary end point in this study primarily comprised PSA measurements. The authors acknowledge the duration of the study was insufficient to demonstrate the impact of dutasteride on survival or delay in bone metastases. The value of PSA measurements as a primary end point of this study rely on two assumptions: (1) PSA kinetics represent a surrogate for metastatic disease, and (2) these measurements do not affect treatment decisions. To justify that a serial rise in PSA levels after definitive treatment can be used as a surrogate for metastatic disease, the authors cited the study by Pound et al. [7] in which PSA kinetics were shown to predate the development of clinically or radiographically detectable metastatic disease by many years. However, the study by Pound et al. comprised patients treated by radical prostatectomy and who were naive to hormonal therapy [7], and the results cannot necessarily be generalized to the cohort in the Schro¨der et al. study. Therefore, the use of PSA-related end points to evaluate the impact of dutasteride on disease progression remains a problem because dutasteride induces PSA changes in benign prostate tissue. Presumably, the delay in doubling time can be explained by the effect of dutasteride on residual prostate tissue locally or on regional metastatic disease. Although the finding that 5-ARI therapy have an impact on treated prostate tissue is novel, it is unclear whether the potentially varying quality of surgical and radiation therapy across 64 centers and 9 European countries, contributing to the presence of residual untreated prostate tissue, is a confounding factor. Hormonal manipulation of PCa after definitive treatment is not without harm, and adverse effects are especially relevant in patients who experience biochemical recurrence in the absence of symptoms. Importantly, the long-term benefit of hormonal therapy in this setting is unclear because progression to CRPC can be inevitable. PCa is a leading cause of cancer mortality in men worldwide, and those who die of it die of metastatic CRPC. An underrecognized late manifestation of PCa is the development of neuroendocrine prostate cancer (NEPC), which is associated with aggressive disease and a poor prognosis [8]. NEPC may constitute 25% of advanced PCa, according to autopsy findings [9]. Therefore, it is important to consider whether hormone therapy promotes the transformation from
789
prostate adenocarcinoma to NEPC, which may arise as a mechanism of resistance. The horizon of harms should extend beyond the early treatment period and include possible adverse impact on future therapy. While the mechanism of action of 5-ARIs is distinct from that of androgen deprivation, the impact of prior exposure to these drugs on the efficacy of AR-targeting therapy has yet to be elucidated. In this exciting era of the rise of potent AR-targeted agents, there is hope that these agents can demonstrate efficacy earlier in the clinical spectrum of advanced PCa and prior to castration resistance. Although the scientific community remains eager to provide an earlier intervention for patients with elevated PSA after definitive therapy, it remains critical to weigh the harm of treatment against the uncertain benefits to patients. Meanwhile, physicians are responsible for critically evaluating the current evidence and explaining the complicated risks and benefits of early intervention. Until more studies are performed with objective end points of survival, physicians are not supported with evidence to recommend 5-ARI therapy for men who experience biochemical recurrence after definitive therapy. Conflicts of interest: The authors have nothing to disclose.
References [1] Shore N, Mason M, de Reijke TM. New developments in castrateresistant prostate cancer. BJU Int 2012;109(Suppl 6):22–32. [2] Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291:944–9. [3] Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24. [4] Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:1192–202. [5] Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, doubleblind, placebo-controlled trial. Lancet 2012;379:1103–11. [6] Schro¨der F, Bangma C, Angulo JC, et al. Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS). Eur Urol 2013; 63:779–87. [7] Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7. [8] Hirano D, Okada Y, Minei S, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol 2004;45:586–92, discussion 592. [9] Aparicio A, Logothetis CJ, Maity SN. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Discov 2011;1:466–8. http://dx.doi.org/10.1016/j.eururo.2012.12.035
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the article published on pp. 779–787 of this issue
5-Alpha Reductase Inhibitors in Prostate Cancer: From Clinical Trials to Clinical Practice Behfar Ehdaie a, Karim A. Touijer a,b,* a
Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; b Department of Urology, Weill Medical College of
Cornell University, New York, NY, USA
After a gap of nearly a decade since the introduction of docetaxel, the past 2 years have seen a tremendous expansion of effective new therapeutic agents for castration-resistant prostate cancer (CRPC). These agents have demonstrated advantages in specific outcomes, including longer survival and relief from disease manifestations such as bone pain [1]. Despite questions regarding the proper sequencing of these agents and their integration into an overall treatment plan, the new agents have immediate clinical utility for the management of CRPC. Advances in our understanding of the molecular pathways and genetic factors underlying prostate cancer (PCa) have been primarily responsible for the identification of new targets, new drugs, and new therapeutic strategies. The role of androgen-receptor signaling in particular has received renewed attention. Concurrently, the sharp rise in the incidence of low-risk PCa during the prostate-specific antigen (PSA) era, and the paradigm shift in the management of localized PCa toward active surveillance have led to an evolution of traditional hormonal therapy, specifically 5-a reductase inhibition (5-ARI). The 5-a reductase enzyme is responsible for converting testosterone into dihydrotestosterone, thereby initiating embryologic development of the prostate, growth of prostate glands, and promotion of PCa [2]. In contrast to the newly discovered agents for CRPC, 5-ARIs have not gained wide acceptance in clinical practice despite some evidence of clinical efficacy. Two landmark randomized controlled trials of finasteride and dutasteride demonstrated an advantage in the primary prevention of PCa [3,4]. In secondary prevention, a recent randomized controlled trial in men with very low-risk PCa treated with
active surveillance with or without dutasteride, dutasteride reduced the time to pathologic or therapeutic progression by 38.9%, compared with placebo [5]. Unfortunately, the results of these trials are complicated by controversy regarding end points. The primary prevention studies have been criticized for lack of generalizability because the results were driven largely by mandatory end-of-study prostate biopsies, preferential benefit in preventing lowgrade cancers that do not have an impact on survival, and increased risk of high-grade disease. The secondary prevention study relied on a composite end point for progression (pathologic progression via biopsy or initiation of therapy) and because subjects and investigators were not blind to PSA results, which triggered treatment decisions [5]. In this issue of European Urology, Schro¨der et al. describe the results of a randomized controlled trial evaluating the efficacy of dutasteride in delaying PSA progression in patients with biochemical failure after definitive therapy [6]. Overall, 187 of the 294 men with PSA failure after radical prostatectomy or radiation therapy who were enrolled in the study completed the 24-mo treatment; 107 discontinued treatment prematurely, mainly due to disease progression. The primary end point of the study was time to PSA doubling, and patients who received dutasteride had a significant delay in time to PSA doubling, with a 66.1% relative risk reduction compared with those who received placebo once daily. In addition, dutasteride significantly delayed disease progression compared with placebo, with a relative risk reduction of 59%. The secondary end point of disease progression, however, comprised multiple criteria (ie, number of days between
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2012.11.006. * Corresponding author. Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Tel. +1 646 422 4486; Fax: +1 212 988 0768. E-mail address: [email protected] (K. Touijer). 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 63 (2013) 788–791
the start of treatment and the earliest of any of the following: PSA doubling time 3 mo, or PSA level >20 ng/ml for patients who underwent primary radiotherapy or >10 ng/ml for patients who underwent radical prostatectomy with or without salvage radiotherapy, associated with a 50% increase from baseline PSA level and confirmed in an immediate subsequent PSA measurement, if available; any biopsy-confirmed progression in the clinical T stage; need for additional rescue therapy for PCa; metastatic disease confirmed by bone scan). In fact, fewer than eight patients had measurable progression of disease defined by identification of bone metastases on imaging or biopsy-proven progression. Therefore, the secondary end point in this study primarily comprised PSA measurements. The authors acknowledge the duration of the study was insufficient to demonstrate the impact of dutasteride on survival or delay in bone metastases. The value of PSA measurements as a primary end point of this study rely on two assumptions: (1) PSA kinetics represent a surrogate for metastatic disease, and (2) these measurements do not affect treatment decisions. To justify that a serial rise in PSA levels after definitive treatment can be used as a surrogate for metastatic disease, the authors cited the study by Pound et al. [7] in which PSA kinetics were shown to predate the development of clinically or radiographically detectable metastatic disease by many years. However, the study by Pound et al. comprised patients treated by radical prostatectomy and who were naive to hormonal therapy [7], and the results cannot necessarily be generalized to the cohort in the Schro¨der et al. study. Therefore, the use of PSA-related end points to evaluate the impact of dutasteride on disease progression remains a problem because dutasteride induces PSA changes in benign prostate tissue. Presumably, the delay in doubling time can be explained by the effect of dutasteride on residual prostate tissue locally or on regional metastatic disease. Although the finding that 5-ARI therapy have an impact on treated prostate tissue is novel, it is unclear whether the potentially varying quality of surgical and radiation therapy across 64 centers and 9 European countries, contributing to the presence of residual untreated prostate tissue, is a confounding factor. Hormonal manipulation of PCa after definitive treatment is not without harm, and adverse effects are especially relevant in patients who experience biochemical recurrence in the absence of symptoms. Importantly, the long-term benefit of hormonal therapy in this setting is unclear because progression to CRPC can be inevitable. PCa is a leading cause of cancer mortality in men worldwide, and those who die of it die of metastatic CRPC. An underrecognized late manifestation of PCa is the development of neuroendocrine prostate cancer (NEPC), which is associated with aggressive disease and a poor prognosis [8]. NEPC may constitute 25% of advanced PCa, according to autopsy findings [9]. Therefore, it is important to consider whether hormone therapy promotes the transformation from
789
prostate adenocarcinoma to NEPC, which may arise as a mechanism of resistance. The horizon of harms should extend beyond the early treatment period and include possible adverse impact on future therapy. While the mechanism of action of 5-ARIs is distinct from that of androgen deprivation, the impact of prior exposure to these drugs on the efficacy of AR-targeting therapy has yet to be elucidated. In this exciting era of the rise of potent AR-targeted agents, there is hope that these agents can demonstrate efficacy earlier in the clinical spectrum of advanced PCa and prior to castration resistance. Although the scientific community remains eager to provide an earlier intervention for patients with elevated PSA after definitive therapy, it remains critical to weigh the harm of treatment against the uncertain benefits to patients. Meanwhile, physicians are responsible for critically evaluating the current evidence and explaining the complicated risks and benefits of early intervention. Until more studies are performed with objective end points of survival, physicians are not supported with evidence to recommend 5-ARI therapy for men who experience biochemical recurrence after definitive therapy. Conflicts of interest: The authors have nothing to disclose.
References [1] Shore N, Mason M, de Reijke TM. New developments in castrateresistant prostate cancer. BJU Int 2012;109(Suppl 6):22–32. [2] Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291:944–9. [3] Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24. [4] Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:1192–202. [5] Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, doubleblind, placebo-controlled trial. Lancet 2012;379:1103–11. [6] Schro¨der F, Bangma C, Angulo JC, et al. Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS). Eur Urol 2013; 63:779–87. [7] Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7. [8] Hirano D, Okada Y, Minei S, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol 2004;45:586–92, discussion 592. [9] Aparicio A, Logothetis CJ, Maity SN. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Discov 2011;1:466–8. http://dx.doi.org/10.1016/j.eururo.2012.12.035