Quo Vadis: Advanced Prostate Cancer Clinical Care and Clinical Research in the Era of Multiple Androgen Receptor-Directed Therapies

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1 Review Article Quo Vadis: Advanced Prostate Cancer Clinical Care and Clinical Research in the Era of Multiple Androgen Receptor-Directed Therapies Won Kim, MD; and Charles J. Ryan, MD The novel androgen receptor-directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration-resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor-directed therapies, such as ARN-509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable. Although advances in genomic technologies have led to unprecedented understanding of the biology of castration-resistant prostate cancer, efforts only now are underway to elucidate the mechanisms of resistance associated with abiraterone and enzalutamide. A tremendous challenge in the near future will be to determine the optimal sequence or combination of therapies to overcome resistance mechanisms. In this review, the current landscape of androgen receptor-directed therapies and future directions necessary to enhance their clinical efficacy for the maximal benefit of patients are discussed. Cancer 2015;121: VC 2014 American Cancer Society. KEYWORDS: metastatic castration-resistant prostate cancer, abiraterone acetate, enzalutamide, biomarkers. INTRODUCTION Prostate cancer is the second most commonly diagnosed malignancy in men and is responsible for >250,000 cancerrelated deaths worldwide. 1 Although surgery and radiotherapy offer curative potential for men with localized prostate cancer, men with advanced prostate cancer are burdened with an incurable disease. Androgen-deprivation therapy (ADT) is the standard of care for men with advanced prostate cancer and has been so for more than 70 years. 2 Unfortunately, virtually all men who receive ADT eventually experience progression to the lethal form of the disease: metastatic castrationresistant prostate cancer (mcrpc). Typically, death occurs 2 to 4 years after the onset of castration-resistance. Docetaxel received regulatory approval in 2004 as the first therapy to prolong overall survival in patients with mcrpc. 3 Since 2010, 5 additional agents cabazitaxel, 4 sipuleucel-t, 5 abiraterone acetate, 6,7 enzalutamide, 8,15 and radium have demonstrated profound survival impact on the lives of patients with mcrpc and have received regulatory approval (Table 1). Among these, the novel androgen receptor (AR)-targeted therapies abiraterone acetate and enzalutamide have the broadest clinical use. These therapies have provided new promise to patients with advanced prostate cancer; however, mcrpc remains incurable, causing great physical, emotional, and financial burdens. In this review, we examine the current landscape of AR-targeted therapies and how it may shape the future of clinical research and care of patients with advanced prostate cancer. Current Landscape of AR-Targeted Therapies Abiraterone acetate Cytochrome P450 17A1 (CYP17A1) is the rate-limiting enzyme in gonadal and extragonadal (ie, adrenal glands, prostate) androgen synthesis. Abiraterone acetate, the prodrug of abiraterone, is a potent CYP17A1 inhibitor that suppresses circulating serum androgens beyond what is possible through ADT alone (Fig. 1). In a phase 3 study of men with mcrpc postchemotherapy (COU-AA-301), treatment with the combination of abiraterone and prednisone improved survival compared with prednisone alone (14.8 months vs 10.9 months; hazard ratio [HR], 0.65; P<.001), leading to its initial regulatory approval in All secondary endpoints favored the patients who received abiraterone, including the time to prostate-specific antigen (PSA) progression (TPP) (10.2 months vs 6.6 months; P<.001), progression-free survival (PFS) (5.6 months vs 3.6 months; P<.001), and the PSA response rate (PSA decline 50%: 29% vs 6%; P<.001). In a Corresponding author: Charles J. Ryan, MD, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, 1600 Divisadero Street, San Francisco, CA, 94115; Fax: (415) ; ryanc@medicine.ucsf.edu Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California DOI: /cncr.28929, Received: February 25, 2014; Revised: June 20, 2014; Accepted: June 30, 2014, Published online September 18, 2014 in Wiley Online Library (wileyonlinelibrary.com) Cancer February 1,

2 Review Article TABLE 1. Phase 3 Studies Demonstrating Improved Survival in Patients With Metastatic Castrate-Resistant Prostate Cancer Regimens (Study Name) Reference Primary Endpoint Notes Docetaxel and prednisone vs mitoxantrone and prednisone (TAX-327) Tannock OS, 18.9 mo vs 16.5 mo (HR, 0.76; P 5.009) Sipuleucel-T vs placebo (IMPACT) Kantoff OS, 25.8 mo vs 21.7 mo (HR, 0.78; P 5.03) Cabazitaxel and prednisone vs mitoxantrone and prednisone (TROPIC) Abiraterone and prednisone vs placebo and prednisone (COU-AA-301) de Bono de Bono OS, 15.1 mo vs 12.7 mo (HR, 0.70; P<.0001) OS, 14.8 mo vs 10.9 mo (HR, 0.65; P<.001) Enzalutamide vs placebo (AFFIRM) Scher OS, 18.4 mo vs 13.6 mo (HR, 0.63; P<.001) Abiraterone and prednisone vs placebo and prednisone (COU-AA-302) Ryan OS, NYR vs mo (HR, 0.75; P 5.01); rpfs, 16.5 mo vs 8.3 mo (HR, 0.53; P<.001) Radium-223 vs placebo (ALSYMPCA) Parker OS, 14.0 mo vs 11.2 mo (HR, 0.70; P 5.002) Enzalutamide vs placebo (PREVAIL) Beer OS, 32.4 mo vs 30.2 mo (HR, 0.70; P<.0001); rpfs, NYR vs 3.9 mo (HR, 0.19; P<.0001) First phase 3 study to demonstrate a survival benefit in mcrpc Accrual between August 2003 and November 2007; asymptomatic or minimally symptomatic; chemotherapy-naive or postchemotherapy Accrual between January 2007 and October 2008; progressive disease after docetaxel Accrual between May 2008 and July 2009; progressive disease after docetaxel Accrual between September 2009 and November 2010; progressive disease after docetaxel; use of prednisone permitted but not required Accrual between April 2009 and June 2010; chemotherapy-naive; asymptomatic or minimally symptomatic; no prior ketoconazole (7 d); patients with visceral metastases were excluded Two or more bone metastases; no visceral metastases; postdocetaxel (or ineligible or unavailable); symptomatic disease Accrual between September 2010 and September 2012; chemotherapy-naive; use of prednisone permitted but not required; no prior abiraterone or ketoconazole; asymptomatic or minimally symptomatic; patients with visceral disease (including liver or lung metastases) were eligible Abbreviations: HR, hazard ratio; mcrpc, metastatic castration-resistant prostate cancer; NYR, not yet reached; OS, overall survival; rpfs, radiographic progression-free survival. second phase 3 study among chemotherapy-naive men with mcrpc (COU-AA-302) in which the coprimary endpoints were radiographic PFS (rpfs) and overall survival (OS), abiraterone again was superior to placebo (rpfs: HR, 0.43; 95% confidence interval [CI], ; P<.001; OS: HR, 0.75; 95% CI, ; P<.01). 7 Secondary endpoints, including risk of decline in Eastern Cooperative Oncology Group performance status, time to the initiation of cytotoxic chemotherapy, time to opiate use for cancer-related pain, and TPP, favored the abiraterone arm. Abiraterone requires the concomitant administration of prednisone to mitigate toxicities that result directly from the potent inhibition of CYP17A1 and the compensatory rise in adrenocorticotropic hormone, which leads to dramatically increased levels of adrenal steroid hormones upstream of CYP17A1 with potent mineralocorticoid activity. 10,11 Therefore, in addition to the side effects caused by mineralocorticoid excess, such as hypertension, hypokalemia, and edema, the potential toxicities associated with long-term prednisone use must be considered for patients who are under consideration for abiraterone treatment. Furthermore, recent investigations regarding ligand-receptor promiscuity of nuclear hormone receptors 12,13 and its potential role in therapeutic response and resistance raises further questions regarding steroid use. However, the clinical application of that work requires further clinical validation. Enzalutamide Enzalutamide is a novel antiandrogen that antagonizes the AR more potently than the previous generation of antiandrogens (eg, bicalutamide). Preclinical studies have 362 Cancer February 1, 2015

3 AR-Directed Therapies in Prostate CA/Kim and Ryan Figure 1. Androgen-receptor (AR)-directed therapies and mechanisms of action are illustrated, including novel androgen synthesis inhibitors and antiandrogens, and their mechanisms of action. Orteronel is a selective 17a-hydroxylase/C (17,20-lyase) inhibitor, but it loses its selectivity at high concentrations. Galeterone is a selective 17,20-lyase inhibitor and also acts as an AR antagonist and increases the rate of AR degradation. DOC indicates docetaxel; 17-OH, 17-hydroxy; CFG 920, a nonsteroidal cytochrome P inhibitor; VT 464, a nonsteroidal selective inhibitor of 17,20-lyase; ARN 909, an AR antagonist; ODM-201, an antiandrogen; AZD 3514, an oral drug that modulates AR signaling. demonstrated that enzalutamide binds to the AR with 8- fold greater affinity than bicalutamide and is active as an inhibitor in cells with AR amplification and cells in which bicalutamide has agonist activity. 14 Administered orally on a daily schedule, enzalutamide is generally well tolerated even in long-term use. In a randomized phase 3 study of 1199 men with mcrpc who had progressed after docetaxel chemotherapy (AFFIRM), enzalutamide demonstrated significantly improved OS compared with placebo (18.4 months vs 13.6 month; HR, 0.63; P<.001), leading to early unblinding of the study. 8 Enzalutamide was superior to placebo for all secondary endpoints, including PSA response rate (54% vs 2%; P<.001), soft tissue response rate (29% vs 4%; P<.001), and rpfs (8.3 months vs 2.9 months; HR, 0.40; P<.001). Enzalutamide received regulatory approval in 2013 in the postchemotherapy setting. A second phase 3 study of enzalutamide versus placebo in chemotherapy-naive patients with mcrpc (PRE- VAIL) focused on the coprimary endpoints of rpfs and OS. 15 Enzalutamide demonstrated a significant benefit in both endpoints, with a 30% reduction in the risk of death (HR, 0.70; P<.0001) and an 81% reduction in the risk of radiographic progression or death (HR, 0.19; P<.0001). The median OS was 32.4 months in the enzalutamide arm versus 30.2 months in the placebo arm. In the AFFIRM study, 5 of 800 patients who received enzalutamide had seizures, and there were no seizures in the control arm. In the PREVAIL study, 2 patients had seizures (1 patient in each study arm). Enzalutamide is known to cross the blood-brain barrier, and it is possible that it lowers the seizure threshold in some patients. Although rare, patients who have a history of seizures or other predisposition to seizures should not receive enzalutamide. Cancer February 1,

4 Review Article Considerations The postchemotherapy phase 3 studies of abiraterone and enzalutamide were placebo-controlled (placebo plus prednisone in the abiraterone study), because there were no standard-of-care treatment options known to prolong survival in this disease setting. However, it is fair to question whether placebo was the appropriate control for the prechemotherapy phase 3 trials of these drugs. The clinical benefit of docetaxel was known for years before those trials, and sipuleucel-t demonstrated its survival benefit in a phase 3 trial that was published before the enrollment period of the PREVAIL study (COU-AA-302 had completed enrollment before publication). That said, prostate cancer is a disease of older men, and many patients with mcrpc do not receive chemotherapy because of comorbidities, toxicities, or patient preferences. Sipuleucel-T is an option only for patients who have asymptomatic (or minimally symptomatic) mcrpc and does not impact the time to disease progression. Thus, abiraterone and enzalutamide represent effective and tolerable options for many patients, and their broad clinical use currently serves as evidence that the studies were conducted in a population in dire need. In addition, the phase 3 chemotherapy-naive studies used coprimary efficacy endpoints of rpfs and OS. rpfs was defined as freedom from death from any cause and freedom from progression of soft tissue or bone lesions. 7 The rationale for using rpfs as a coprimary endpoint stems from the finding that mcrpc is a disease with long median OS, 16 with multiple clinical events (eg, PSA progression, radiographic progression, decline in functional status, need for cytotoxic chemotherapy) that occur before death. Thus, the addition of rpfs to OS as a coprimary endpoint may provide a more comprehensive assessment benefit attributable an intervention. Both abiraterone and enzalutamide demonstrated significant improvement in rpfs. Enzalutamide also improved OS compared with placebo in this patient population; abiraterone demonstrated a strong trend toward OS improvement, but it fell short of statistical significance. Nevertheless, in the United States, the label for abiraterone was expanded to the chemotherapy-naive space based on these results; enzalutamide just recently received US FDA approval for its expanded indication after a priority review. AR-Directed Therapies in Development: Androgen Synthesis Inhibitors Orteronel (TAK-700) Orteronel, an imidazole derivative, is also an inhibitor of CYP17A1 although, unlike abiraterone, it is a nonsteroidal and reversible inhibitor. In addition, it is highly selective for 17,20-lyase (although, at higher concentrations, it does lose some selectivity and also inhibits 17a-hydroxylase). 17 A theoretical advantage of selective 17,20-lyase inhibition is that it may obviate the need for corticosteroid administration to mitigate the side effects associated with mineralocorticoid excess; the approved label for abiraterone acetate requires the daily coadministration of 10 mg prednisone. A phase 1/2 study in 96 patients with mcrcp demonstrated that orteronel (at various dose cohorts, including patients who did or did not receive prednisone) is well tolerated. The most common grade 3 adverse events were fatigue (9%) and diarrhea (3%). Orteronel also was clinically active, and 41% to 63% of patients (at various dose cohorts) achieved a PSA decline 50%. 18 It is noteworthy that the side-effect profile was similar to that of abiraterone acetate. Based on these data, 2 phase 3 studies of orteronel were initiated in patients with mcrpc (before and after docetaxel, mirroring the abiraterone and enzalutamide experiences). An interim analysis of the postchemotherapy study (ELM-PC 5) resulted in early termination for failing to satisfy the primary endpoint of improved OS. 19 It is worth noting that the median OS in patients who received orteronel was 17.0 months versus 15.2 months for patients who received placebo (HR, 0.88; 95% CI, ; P5.1898), comparing favorably to the abiraterone experience in similar patients. There were no safety concerns. 20 Similarly, results from the interim analysis of orteronel in patients with chemotherapy-naive mcrpc (ELM-PC 4) failed to demonstrate a significant improvement in OS, although it did produce a significant improvement in rpfs. 21 One of the reasons posited for the negative findings in those studies is that efficacious poststudy treatments became available during the study periods, as discussed further below. Currently, a randomized, phase 3, cooperative group study of orteronel with or without ADT in patients with metastatic, hormonesensitive prostate cancer is ongoing (National Clinical Trials [clinicaltrials.gov] identifier NCT ). Galeterone (TOK-001) Galeterone is a potent CYP17A1 inhibitor that, in preclinical studies, has demonstrated greater potency than abiraterone acetate. 22 In addition, galeterone has potent, direct ARantagonist activity as well as the effect of AR downregulation. Therefore, galeterone interrupts AR activity through multiple mechanisms. In a phase 1 study of 49 patients with mcrpc, galeterone was safe and well 364 Cancer February 1, 2015

5 AR-Directed Therapies in Prostate CA/Kim and Ryan tolerated, with grade 3 and 4 adverse events occurring at a frequency of 8% and 1%, respectively, and 11 patients (22%) had a PSA decline 50%. A phase 2 study of galeterone in patients with mcrpc is ongoing (NCT ). AR-Directed Therapies in Development: Antianderogens ARN-509 Like enzalutamide, ARN-509 is a potent AR antagonist that does not demonstrate significant AR-agonist activity, 23 particularly in the presence of amplified AR, which is common in the castration-resistant setting. 24 In prostate cancer cell lines, ARN-509 bound to AR with 5-fold to 10-fold greater affinity than bicalutamide; and, in murine xenograft models of mcrpc, it demonstrated greater antitumor activity than enzalutamide, with pharmacokinetic characteristics that potentially predicted a higher therapeutic index (maximal efficacy observed at lower steady-state plasma and brain levels compared with enzalutamide). In a phase 1 study of 39 patients with progressive mcrpc, ARN-509 was safe and well tolerated, with 4 grade 3 adverse events reported (3 which were considered unrelated to treatment; no seizures were reported). ARN-509 demonstrated clinical efficacy: 18 patients (60%) demonstrated a PSA decline 50%, and 5 of 10 evaluable patients who had measureable soft tissue lesions had a response of stable disease after >6 months. 25 Preliminary results from the phase 2 study, at the recommended ARN-509 dose of 240 mg daily, were reported in Forty-six chemotherapy-naive patients with mcrpc (25 treatment-naive, 21 postabiraterone therapy) were enrolled; and, at 12 weeks, 88% of the treatment-naive patients and 29% of the postabiraterone patients experienced a PSA response according to Prostate Cancer Clinical Trials Working Group (PCWG-2) criteria. 26 The phase 2 study also enrolled 47 patients with nonmetastatic CRPC, and 91% of those patients experienced a PSA response at 12 weeks. 27 Ongoing studies of ARN-509 include: a phase 3, placebo-controlled trial of ARN-509 in patients with nonmetastatic CRPC (NCT ); a phase 1b trial of ARN-509 in combination with abiraterone acetate and prednisone (NCT ); and a phase 2 randomized trial of ARN-509 in patients with biochemically relapsed, hormone-sensitive prostate cancer (NCT ). In the Pipeline There are multiple AR-directed therapies in early stages of clinical development. These include the following: 1. CFG-920, a nonsteroidal CYP17 inhibitor, currently in a phase 1/2 clinical trial (NCT ); 2. VT-464, a nonsteroidal selective inhibitor of 17,20- lyase, currently in a phase 1 trial (NCT ); 3. ODM-201, an antiandrogen that, in preclinical models, does not cross the brain-blood barrier, currently in a phase 2 clinical trial (NCT ); 4. AZD-3514, an oral drug that modulates AR signaling by 1) inhibition of AR nuclear translocation; and 2) down-regulation of AR levels 28 ; AZD-3514 is in a phase 1 clinical trial (NCT ); and 5. EZN-4176, an antisense oligonucleotide that binds to and degrades AR messenger RNA, leading to decreased AR expression; the phase 1 study was suspended, because dose escalation was limited by toxicities. 29 The profound impact demonstrated by abiraterone acetate and enzalutamide and the promising clinical activity of many AR-targeted drugs in development offer promise to the many patients burdened by advanced prostate cancer. However, to maximize the benefits of these therapies, further investigations are necessary on many fronts. Resistance to AR-Directed Therapies The oncogenic landscape of prostate cancer continues to be explored and charted through efforts fueled by advances in next-generation sequencing, leading to unprecedented understanding of the genetic basis of prostate cancer, providing investigators with a glimpse of the incredible molecular and clinical heterogeneity of the disease, and offering the possibility of precision medicine. However, in the era of targeted therapies, it is now necessary to take into account that the biology of prostate cancer that is resistant to abiraterone or enzalutamide (or both) is likely to be distinct from the disease that was previously termed simply castration-resistant prostate cancer (CRPC). Resistance to abiraterone and enzalutamide typically develops within 6 to 18 months of treatment initiation. Preclinical studies and increasing widespread clinical experience with these agents are elucidating various mechanisms of resistance associated with AR-targeted therapy, and similar resistance is expected for the AR-targeted therapies currently in development. Key potential resistance mechanisms against novel AR-directed therapies include further up-regulation of CYP17A1 activity and steroidogenesis 35,36 ; alterations in the AR itself, including AR mutations 37,38 and splice variants 35,39 that may promote ligand-independent activation of the AR signaling cascade; the promiscuous behavior of nuclear receptors, 13 including Cancer February 1,

6 TABLE 2. Proposed Disease States Within Castration-Resistant Prostate Cancer Ligand Dependent? AR Dependent? CRPC Mechanism Potential Clinical Scenario Yes Yes Increased androgen synthesis through overexpression of CYP17A1 or other steroidogenic enzymes No Yes AR mutation or splice variant allowing ligand-independent AR activation Yes No Ligand-mediated activation of alternative nuclear receptor Patient with disease progression after ketoconazole; experiences clinical response to more potent CYP17A1 inhibition with abiraterone acetate Patient has progression of disease after enzalutamide; mutational analysis reveals AR F876L mutation Patient experiencing disease progression after enzalutamide; analysis reveals induction of glucocorticoid receptor No No Neuroendocrine/small cell phenotype Patient progressing after multiple therapies; low/no PSA production; genomic analysis with MYC amplification or AURKA expression Abbreviations: AR, androgen receptor; AURKA, aurora kinase A; CRPC, castration-resistant prostate cancer; CYP17A1, cytochrome P450, family 17, subfamily A, polypeptide 1; FL, phenylalanine to leucine substitution at amino acid position 876 of the AR polypeptide; MYC, v-myc avian myelocytomatosis viral oncogene homolog; PSA, prostate-specific antigen. the recent finding that glucocorticoid receptor expression is induced in the setting of antiandrogen therapy 12 ; activation of non-ar pathways, such as the phosphoinositide 3- kinase (PI3K) and v-myc myelocytomatosis viral oncogene homolog (MYC) pathways 40,41 ; and phenotypic differentiation into a neuroendocrine or anaplastic phenotype. 42,43 Efforts are underway to understand mechanisms of resistance associated with the targeted treatment of advanced prostate cancer, and AR-directed therapies are a particular focus, including the 2 Stand Up 2 Cancer-Prostate Cancer Foundation Dream Team projects. 44,45 The promise of these efforts, which rely on multicenter expertise and collaboration, have generated great excitement. In addition, CRPC, which, over the past decade, has become the standard umbrella term to describe the disease state after progression on primary ADT, may no longer be adequate in this era of multiple therapeutic options. Terms that describe the disease state with regard to both the ligand and the receptor may be necessary to convey the disease biology (Table 2). For example, androgen-dependent, receptor-dependent CRPC may describe a cancer that has progressed after abiraterone but remains dependent on increased steroidogenesis; whereas androgen-independent, receptor-dependent CRPC may describe prostate cancer that has progressed through an AR variant that allows ligand-independent activation. 46 Sequential and Combination Therapy In light of the resistance mechanisms associated with ARdirected therapy, clinician investigators have initiated studies (Table 3) to answer 2 key questions: First, what is the optimal sequencing of therapy; and, second, what is the role of combination therapy? Sequencing The first phase 3 studies of both abiraterone acetate and enzalutamide were conducted in postchemotherapy patients and excluded prior receipt of the other agent. In the COU-AA-301 study, the PSA response rate was 29%, the median time to PSA progression was 10.2 months, and the median rpfs was 5.6 months. By comparison, in the COU-AA-302 study, the PSA response rate was 62%, the median time to PSA progression was 11.1 months, and the rpfs was 16.5 months. Similarly, in the AFFIRM study, the PSA response rate was 54%, the median time to PSA progression was 8.3 months, and the median rpfs was 8.3 months. In the PREVAIL study, the PSA response rate was 78%, the median time to PSA progression was 11.2 months, and the median rpfs was not yet reach (the lower bound of the 95% CI was 13.8 months). In addition, in retrospective analysis, the clinical activity of docetaxel after disease progression on abiraterone appeared to be less than expected. 47 Although any direct comparisons of these results are not conclusive, along with preclinical evidence pointing to the potential cross-resistance between AR-directed therapies and taxanes, 48 at least they raise the issue of sequencing these agents. Whether a clinical trial is appropriate to answer this question is up for debate. Based on the magnitude of benefit in the prechemotherapy setting, abiraterone has already been approved in the prechemotherapy space, and it is likely that enzalutamide will follow shortly. The early clinical use of 366 Cancer February 1, 2015

7 AR-Directed Therapies in Prostate CA/Kim and Ryan TABLE 3. Current Clinical Investigations in Sequential and Combination Therapies for Advanced Prostate Cancer Sequencing studies Chemotherapy-naive mcrpc NCT : Concurrent vs sequential treatment with sipuleucel-t and enzalutamide in mcrpc Chemotherapy-naive or postchemotherapy mcrpc NCT : Concurrent vs sequential treatment with sipuleucel-t and abiraterone in men with mcrpc Combination studies AR therapies Chemotherapy-naive mcrpc NCT : A phase 3 study of enzalutamide with or without abiraterone in patients with mcrpc Chemotherapy-naive or postchemotherapy mcrpc NCT : A phase 1 study of ARN-509 in combination with abiraterone in mcrpc AR and non-ar therapies Chemotherapy-naive mcrpc NCT : A phase 1 study of enzalutamide and docetaxel in men with advanced prostate cancer NCT : Abiraterone acetate with or without dasatinib in treating patients with mcrpc NCT : A study of cabozantinib in combination with abiraterone in patients with bone-metastatic CRPC NCT : A phase 2 study of AMG386 and abiraterone in patients with mcrpc NCT : ARN509 plus everolimus in men with progressive metastatic castration-resistant prostate cancer after treatment with abiraterone acetate Chemotherapy-naive or postchemotherapy mcrpc NCT : A phase 1/2 study of HSP90 inhibitor AT13387 alone or in combination with abiraterone NCT : A phase 2 study of abiraterone with or without veliparib in treating patients with mcrpc NCT : BKM120 and abiraterone for patients with mcrpc Postchemotherapy mcrpc NCT : A phase 2 study of olaparib with abiraterone in treating mcrpc NCT : A phase 1/2 study of alisertib in combination with abiraterone and prednisone for patients with CRPC after progression on abiraterone NCT : Cabazitaxel and abiraterone in patients with mcrpc NCT : Tivozanib and enzalutamide in advanced prostate cancer Abbreviations: AR, androgen receptor; CRPC, castration-resistant prostate cancer; HSP90, heat-shock protein 90; mcrpc, metastatic castration-resistant prostate cancer; NCT, National Clinical Trials identifier. abiraterone (and even enzalutamide) by clinicians before chemotherapy may obviate this question. A more relevant question may be whether there is a role for sequencing the AR-directed therapies (ie, abiraterone followed by enzalutamide, or vice versa). Retrospective studies have demonstrated moderate clinical activity when 1 AR-directed therapy is followed by the other, with a median PFS of 3 to 4 months. However, there are some patients who do have significant clinical responses after progression on 1 AR-directed therapy, and prior response to abiraterone or enzalutamide is not predictive of a response to the other. Recently reported findings regarding potential mechanisms of resistance to ARtargeted therapies may shed some light. AR-V7 is a constitutively active AR splice variant that is present in patients with mcrpc. In a small study of 62 patients who were about to begin treatment with enzalutamide or abiraterone (31 patients in each arm), the AR-V7 variant was identified in 18 men (29%). 56 None of those 18 patients with the AR-V7 variant experienced a PSA response to either enzalutamide or abiraterone, whereas 27 of the 44 patients (62%) without the variant experienced a PSA response. It is noteworthy that 11 of the 12 AR-V7- positive patients (92%) who were about to begin enzalutamide had previously received abiraterone, and 2 of the 6 AR-V7-positive patients (33%) who were about to begin abiraterone had previously received enzalutamide. Another study evaluated AR amplification status using fluorescence in situ hybridization in 33 patients with mcrpc. 57 In that study, of 16 patients who were abiraterone-naive and enzalutamide-naive, 81% had AR amplification. In 11 patients who were resistant to abiraterone, 9% had AR amplification; and, in 6 patients who were resistant to enzalutamide, 66% had AR amplification. Although these were small studies, they suggest that the mechanisms of resistance to these AR-targeted therapies may indeed be distinct and that AR-V7 or AR amplification status may have a role as a biomarker in predicting response to abiraterone or enzalutamide. Furthermore, AR splice variant or amplification status may be able to determine whether sequencing AR-targeted therapies is a feasible strategy. For example, if the AR-V7 splice variant is identified in a patient who previously received abiraterone, then further treatment with enzalutamide may be futile; or a patient who previously received enzalutamide who retains AR amplification and is AR- Cancer February 1,

8 Review Article V7-negative may yet respond to abiraterone. These are conjectures based on preliminary results from small studies; clearly, prospectively analytical and clinical validation is necessary for any clinical application. However, these exciting findings provide a potential strategy by which clinicians may 1 day make treatment decisions. Combinations In general, combination treatments in advanced prostate cancer have not proven fruitful, although combination approaches with the novel agents discussed above have not yet been thoroughly evaluated. Docetaxel has been combined with calcitriol, 58 risedronate, 59 atrasentan, 60 zibotentan, 61 bevacizumab, 62 aflibercept, 63 and dasatinib 64 in large, randomized, placebo-controlled phase 3 studies, and all studies have been negative. However, it can be pointed out that, in every 1 of those trials, docetaxel was combined with a second agent that had not independently demonstrated survival benefit in patients with mcrpc. The current era, with multiple therapies available that have demonstrated survival benefit and promising therapies in clinical development (particularly ARdirected therapies), offers renewed promise. Rational combination therapies that address the various disease states in mcrpc have the potential to improve clinical outcomes for men with advanced prostate cancer. For example, in androgen-dependent, AR-dependent CRPC, it should be considered whether targeting both androgen synthesis and the AR concurrently can improve outcomes compared with sequential or monotherapy. A phase 3 clinical trial of enzalutamide with or without abiraterone (NCT ) will soon begin to enroll patients. Also, a phase 1 study of ARN-509 with abiraterone is ongoing (NCT ) and may lead to further investigation of this combination. Additional Considerations Another relevant question to be answered is whether the earlier use of AR-directed drugs like abiraterone and enzalutamide may prove to be the optimal use of these agents. A phase 2 trial of enzalutamide monotherapy in men with hormone therapy-naive prostate cancer produced impressive results: at 25 weeks, 93% of patients had a PSA decline 80%, for a median PSA decline of 99.6%. 65 Currently, there are ongoing, randomized phase 3 studies of ADT with or without abiraterone (NCT ) or orteronel (NCT ) in patients with newly diagnosed, metastatic, hormone-naive prostate cancer. Furthermore, studies of abiraterone in the neoadjuvant space have reported promising results, 66,67 and additional studies in both the neoadjuvant and adjuvant settings for high-risk prostate cancer are ongoing (NCT , abiraterone and luteinizing hormone-releasing hormone agonist with or without enzalutamide before surgery; NCT , enzalutamide in patients with high-risk prostate cancer after radical prostatectomy; NCT , enzalutamide, radiation, and hormone therapy for patients with intermediate-risk or high-risk prostate cancer). Looking forward, a fresh perspective on the process of therapy development is in order. Since 2010, 5 new agents have been approved, each or which has demonstrated improved OS in men with mcrpc. Given the paucity of therapeutic options available at the time, the improvement in OS depended largely on the efficacy of the drug in question. Abiraterone and enzalutamide in both the chemotherapy-naive studies and the postchemotherapy phase 3 studies were compared with placebo, as discussed above. Given the current standard of care, placebo will no longer be an acceptable control arm in clinical trials of patients with mcrpc. Appropriate control arms should be determined according to: 1) the patient population, ie, for asymptomatic or minimally symptomatic patients, an appropriate control arm may be sipuleucel-t or the AR-targeted therapies, whereas, in patients with symptomatic disease, chemotherapy may be more appropriate; and 2) the disease state, ie, (in the chemotherapy-naive space, abiraterone or enzalutamide would be reasonable choices, and sipuleucel-t also would be a reasonable choice for in asymptomatic patients; whereas, in the postdocetaxel space, cabazitaxel or radium-223 may be reasonable options. Practically speaking, because the AR-targeted therapies abiraterone and enzalutamide are in broadest clinical use, they may serve as an appropriate control arm for the majority of patient populations. In any case, the bar for improved OS will become more difficult to clear. Furthermore, the efficacy of sequential and subsequent therapies may preclude the further use of OS as a primary clinical trial endpoint, and surrogate and intermediate markers of clinical benefit in mcrpc are needed. This is illustrated in the recently reported results from the ELM-PC5 study of orteronel in postchemotherapy mcrpc and the ELM-PC4 study of orteronel in chemotherapy-naive patients, neither of which met their primary endpoints of efficacy. To further illustrate this point, in ELM-PC5, the median rpfs for the treatment versus placebo arms were 8.3 months and 5.7 months, respectively (HR, 0.76; P ), which is comparable to the median rpfs reported in the phase 3 COU-AA-301 and AFFIRM studies. In addition, the median OS for the placebo arm in the ELM-PC5 study was 368 Cancer February 1, 2015

9 AR-Directed Therapies in Prostate CA/Kim and Ryan longer than that for the placebo arm in the COU-AA-301 study, which may be an indication of a poststudy treatment effect on OS (the placebo arms of most contemporary trials have outperformed those of older trials, and the efficacy of poststudy treatment options available is a major reason). Furthermore, subgroup analyses demonstrated an OS benefit in the non-european and non-north American cohort, in which access to abiraterone was limited (and enzalutamide use was nonexistent). Thus, as novel therapies continue to advance through the clinical development pipeline, investigators must consider whether alternate endpoints (ie, surrogates) should be considered to define the true treatment effect of a drug. 68 For example, the label for abiraterone has been expanded based on the primary endpoint of rpfs. Other candidate surrogates include enumeration of circulating tumor cells, novel imaging biomarkers, and patient-reported outcomes Also, it is possible that these can be used in combination with known prognostic factors, such as serum lactate dehydrogenase and hemoglobin levels. 71 The incorporation of surrogate biomarkers into current clinical trials and practice will require a greater understanding of the molecular and biologic characteristics of advanced prostate cancer, demonstration of analytic and clinical validation (as well as clinical utility) of candidate surrogates, 72 and, finally, integration into prospective clinical trials. Conclusion The success of the novel AR-directed therapies abiraterone acetate and enzalutamide has ushered in a new, promising era in the treatment of advanced prostate cancer. Capitalizing on the finding that retained AR activity is the hallmark of CRPC, additional AR-directed therapies are in development. 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