Urologic Oncology: Seminars and Original Investigations ] (2015) ∎∎∎–∎∎∎
Seminar article
Enzalutamide: Development from bench to bedside R.M. Bambury*, H.I. Scher New York, NY Received 15 December 2014; accepted 31 December 2014
Abstract Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 60 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First-generation compounds such as bicalutamide had only modest efficacy. Furthermore, in the setting of AR overexpression or specific mutations in the AR ligand– binding domain, these early compounds had partial agonist properties and induced disease progression. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types. r 2015 Elsevier Inc. All rights reserved.
Keywords: Enzalutamide; Prostate cancer; MDV3100
Introduction Prostate tissue, both benign and malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation [1]. The therapeutic benefit of targeting this pathway has been apparent since 1941, when Huggins and Hodges [2] reported that reducing androgen levels through surgical castration or exogenous estrogen administration decreased prostate cancer proliferation (as measured by serum acid phosphatase levels) and that exogenous testosterone increased its activity. Palliation of symptoms was also documented in the primary and distant sites [3]. Later, the demonstration in the 1980s that gonadotrophinreleasing hormone analogues produce a medical castration and allow patients to avoid surgical orchiectomy, positioned these compounds as the first-line standard of care for the management of advanced disease: a strategy termed androgen deprivation therapy (ADT) [4]. The biology of prostate cancers progressing on ADT (i.e., castration-resistant prostate cancer [CRPC]) is notable for a number of features that contribute to continued AR Corresponding author. Tel.: þ1-917-355-3984. E-mail address: [email protected] (R.M. Bambury). *
http://dx.doi.org/10.1016/j.urolonc.2014.12.017 1078-1439/r 2015 Elsevier Inc. All rights reserved.
signaling despite castrate levels of serum testosterone (o50 ng/dl). These tumors harbor amplification of the AR gene in 30% of cases and activating AR point mutations in others (the specific types and frequency vary across reports) [5,6]. AR protein is expressed at higher levels in CRPC relative to benign prostate tissue and treatment-naïve prostate cancer [7]. AR splice variants, truncated forms of the AR protein lacking the C-terminal ligand-binding domain, can also emerge, which can activate signaling in the absence of the ligand [8,9]. Furthermore, CRPC can evolve mechanisms that result in high intratumoral androgen levels despite serum levels in the castrate range. Contributing to the high levels are continued production of androgens in the adrenal glands, increased tumor uptake of available circulating androgens, and up-regulation of the androgen biosynthetic machinery in the tumor itself [10,11]. Reciprocal feedback between the AR and mammalian target of rapamycin pathways, the latter altered in upwards of 70% of CRPC cases, also contributes to resistance [12,13]. These and other molecular alterations can sensitize the tumor to lower levels of circulating androgens or enable growth independent of them. The result is that, in most of the cases, CRPC remains dependent on AR signaling. Clinical evidence of this
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includes that the overwhelming majority of CRPCs continue to secrete prostate-specific antigen (PSA), an AR response gene, and that continuation of ADT in CRPC improves median overall survival by 2 to 6 months [14]. First-generation AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the AR molecule. Beginning in the 1970s, a succession of the molecules were developed including cyproterone acetate, flutamide, bicalutamide, and nilutamide, each with activity as single agents in the non–castrate disease setting. Subsequently, each was evaluated in combination with standard ADT (orchiectomy or gonadotrophin-releasing hormone agonist/antagonist therapy) and was ultimately shown to provide, at best, modest improvements in overall outcomes relative to ADT alone [15]. Their effects in CRPC were also modest, with Z50% PSA decline seen in only 25% of cases and few objective tumor regressions [16–18]. Nevertheless, these agents provided further proof that AR signaling could be targeted in CRPC, although more potent molecules were needed, especially given the evidence that over time, they could become agonists, as evidenced by the observation of withdrawal responses when they were discontinued [19]. This was subsequently shown in laboratory models to occur because these agents become agonists in the setting of AR overexpression [20]. The focus of clinical investigation then shifted toward the development of cytotoxic agents, and in 1996, the first cytotoxic—mitoxantrone—was shown to provide palliation of the symptoms in CRPC [21]. This was followed shortly thereafter by tubulin-targeting agents, and in 2004, docetaxel was Food and Drug Administration (FDA) approved based on a survival benefit in 2 landmark phase 3 trials [22,23]. The focus of clinical development in CRPC then shifted to the predocetaxel and postdocetaxel spaces, and the central belief at the time was that these tumors were “hormone refractory” and that there was no role for “hormonal agents” in this disease state. However, some investigators maintained an interest in identifying new and more potent AR signaling blockade strategies and in particular, next-generation antiandrogens with greater AR binding affinity and without agonist effects in tumors with overexpressed AR [20].
Enzalutamide discovery and development Preclinical discovery The effort to develop such a compound began with an experiment whereby a series of 7 matched pre-ADT castration-sensitive and post-ADT castration-resistant prostate cancer cell lines were profiled to identify differences in gene expression [20]. Notable here was that mRNA studies showed that AR was the only gene consistently overexpressed in all 7 lines. Subsequently, Sawyers and Jung used derivatives of the nonsteroidal thiohydantoin AR agonist
RU59063, selected for its high affinity and selectivity for AR over other steroid receptors, in a screen for activity against LNCaP-AR cells with overexpressed AR protein [24]. Nearly 200 derivatives of the compound were synthesized and screened for their ability to inhibit growth and PSA secretion, of which RD162, which was later modified to become MDV3100, was chosen for further study based on oral bioavailability and longer serum halflife. Xenograft studies were performed, which showed that both the compounds had significant antitumor effects in CRPC mouse models with overexpressed AR. Bicalutamide had little or no inhibitory effects in these models, and in some cases, it showed agonist effects. Mechanistically, both enzalutamide and bicalutamide bind AR at its ligandbinding domain to prevent signaling; however, enzalutamide has 4-fold greater binding affinity than bicalutamide and, unique from bicalutamide, inhibits AR translocation to the nucleus and inhibits binding of the ligand-bound receptor complex to DNA (Fig. 1) [24]. Enzalutamide is also active against prostate cancer cell lines bearing the W741C AR point mutation that is known to confer resistance to bicalutamide [24]. Clinical testing Phase I/II clinical trial The first-in-human study of enzalutamide enrolled 140 men with metastatic CRPC across 5 US centers from July 2007 to December 2008 [25]. Importantly, this and subsequent trials incorporated the Prostate Cancer Working Group 2 (PCWG2) recommendations for evaluating systemic treatment approaches in CRPC [26]. The recommendations are based on several key principles: abandon grouped categorizations of response that consider all sites of disease together in favor of reporting outcomes for each manifestation of disease independently (e.g., changes in PSA levels, osseous disease, soft tissue nodal, or visceral disease); when evaluating bone scans, interpret apparent worsening with apparent new lesions on a first follow-up scan carefully by requiring the documentation of new lesions on a second follow-up before considering a patient to have progressed (in the absence of other signs of progression); ensure a drug is no longer working before stopping therapy; and continue treatment despite signs of progression (e.g., slow rises in PSA levels) that are not clinically meaningful. The trial was initially designed as a single-arm phase I study to assess safety, tolerability, and maximum-tolerated dose using a 3 þ 3 rule. However, when PSA level declines were observed in all the first 6 patients, the trial was modified and expanded in both prechemotherapy and postchemotherapy cohorts using a phase I to II design to allow a more robust assessment of treatment efficacy. Doses ranging from 30 to 600 mg/d were tested, and the most common treatment-related grade 3 to 4 adverse events were fatigue (11%) and arthralgia (2%). Seizures were observed
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Fig. 1. Pharmacodynamic effects of enzalutamide and bicalutamide on AR signaling in the setting of AR protein overexpression. Binding affinity of dihydrotestosterone (DHT) is included for comparison. (Reproduced with permission from Yu Chen.)
in 3 (2%) patients, all of whom received doses more than 360 mg daily. Overall, the incidence of these adverse events was increased at doses above 240 mg/d, and there were no seizures recorded at or below this dose level, so it was defined as the maximum-tolerated dose. To illustrate the on-target pharmacodynamic activity of enzalutamide, measurement of androgen to AR binding using F-fluoro-5alpha-dihydrotestosterone (FDHT)-positron emission tomography scans was performed to measure uptake of radiolabeled dihydrotestosterone (FDHT) in 22 patients (Fig. 2). There was a significant decrease in metastatic uptake at all dose levels, demonstrating that enzalutamide was successfully blocking dihydrotestosterone binding to AR and illustrating the on-target effects of the drug. The extent of reduction in FDHT uptake appeared to plateau at a dose of 150 mg/d despite that higher plasma concentrations of drug were seen with higher dose levels. A secondary objective of the study was to assess antitumor activity (Table 1). By manifestation, PSA level decline of Z50% was seen in 61% of chemotherapy-naïve patients and 52% of patients who had received prior chemotherapy (Fig. 3). The declines were seen at all dose levels with a plateau in the degree of decline at 240 mg/d. The importance of the PCWG2 recommendation to not stop therapy based on PSA level changes alone is illustrated by a patient who was continued on treatment with enzalutamide for 3.5 years in the setting of a slowly rising PSA level without radiographic or clinical progression [27]. Circulating tumor cell (CTC, CellSearch) enumeration was
performed at baseline and monthly as a measure of a direct effect of drug on the tumor because of concerns that PSA level declines might merely be owing to blockade of AR signaling independent of an effect on tumor growth. Conversion from unfavorable counts of Z5 CTCs/7.5 ml to favorable counts of 4 or fewer CTCs/7.5 ml was seen in 49% of 51 measurable patients. There was also a 22% partial response rate in soft tissue lesions (the RECIST criteria). Overall, response rates were higher in chemotherapy-naïve patients relative to those who had received prior chemotherapy (Table 1). A dose of 160 mg/d was selected for phase III testing because it appeared to have similar activity to that of higher doses based on FDHT-positron emission tomography, PSA level, and conventional imaging studies and was associated with lower toxicity. Phase III clinical trials The first registration phase III clinical trial (AFFIRM) testing enzalutamide was conducted between September 2009 and November 2010 at 156 sites across 5 countries [28]. A total of 1,199 men with progressive, metastatic CRPC (as per the PCWG2 criteria) who had received prior docetaxel were randomized 2:1 to receive enzalutamide 160 mg/d or placebo. The use of an AR-targeted therapy in the postchemotherapy setting was a paradigm shift when compared with where these agents had typically been used in the past. An independent data safety monitoring committee unblinded the study in November 2011 when a planned
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Fig. 2. FDHT-PET before enzalutamide and after enzalutamide administration in a patient with widespread vertebral bone metastases. PET ¼ positron emission tomography. (Reproduced with permission from Scher et al [25].) (Color version of figure is available online.)
interim analysis showed that enzalutamide was associated with a significant overall survival benefit (hazard ratio for death ¼ 0.63; P ¼ 0.001) (Fig. 4B). Enzalutamide was associated with clinically and statistically significant improvements in PSA response rate (Z50% decline in 54% vs. 2%, P o 0.01), median radiographic progressionfree survival (8.3 vs. 3.0 mo, P o 0.01), and median overall survival (18.4 vs. 13.6 mo, P o 0.01) (Fig. 4A and B and Table 2). Enzalutamide was generally well tolerated, although there was increased incidence of hot flashes (20% vs. 10%), musculoskeletal pain (14% vs. 10%), and headaches (12% vs. 6%) when compared with placebo. Seizures occurred in 5 of 800 patients treated with enzalutamide. Based on these findings, in an expedited review process, the FDA approved enzalutamide for use in patients with CRPC who had received prior chemotherapy in August 2012—less than 2 years after the last patient was enrolled on AFFIRM. A recent update of this trial also demonstrated
that enzalutamide also prolonged median time to first skeletal-related event (13 vs. 17 mo, P ¼ 0.0001, Table 2) [29]. The same update also showed that enzalutamide improved health-related quality of life in 42% of patients when compared with 15% on placebo (P o 0.0001) when measured using the FACT-P score (Table 2) [29]. This validated tool measures quality of life in patients with prostate cancer across 5 domains: physical well-being, functional well-being, social well-being, emotional well-being, and a prostate cancer subscale that measures symptoms such as fatigue and pain [30]. Enzalutamide led to a statistically significant improvement in all the 5 domains when compared with placebo [29]. A prechemotherapy phase III trial followed (PREVAIL), in which enzalutamide was compared with placebo in men with metastatic CRPC who had not received prior cytotoxic chemotherapy [31]. A larger sample size was needed to demonstrate improved overall survival because of the multiple life-prolonging therapies that had become available
R.M. Bambury, H.I. Scher / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–9 Table 1 Efficacy measures for enzalutamide described by disease manifestation (as described by PCWG2) in the initial phase I/II clinical trial No prior chemotherapy (n ¼ 65)
Prior chemotherapy (n ¼ 75)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
62% 41 Weeks
51% (P ¼ 0.23) 21 Weeks (P ¼ 0.01)
Soft tissue Radiographic response (RECIST)
36%
12%
Bone Bone scan stable at 12 weeks 63%
51%
Radiographic PFS (median)
Not reached
29 Weeks (P ¼ 0.01)a
PFS ¼ progression-free survival. a P values refer to comparison between the no prior chemotherapy vs. prior chemotherapy cohorts.
for this disease. Patients were likely to receive some or all of these after progression on protocol-defined therapy, with subsequent dilution of the effect of enzalutamide on the overall survival. In total, 1,717 men were enrolled between September 2010 and September 2012, of whom 485% had received prior antiandrogens such as bicalutamide or nilutamide. After a median follow-up of 22 months, there were again substantial improvements in the proportion of patients achieving a Z50% PSA level decline (78% vs. 3%), median radiographic progression-free survival (not reached vs. 3.9 mo), and median overall survival (not reached vs. 31.0 mo, P o 0.001) (Fig. 4B and C and Table 3). Median time to initiation of chemotherapy was 28 months with enzalutamide vs. 11 months with placebo (P o 0.001) (Table 3). Based on these data, in September 2014, the FDA expanded the indication for enzalutamide to patients with metastatic CRPC regardless of prior therapies. The efficacy outcomes seen with enzalutamide for first-line treatment of metastatic CRPC are listed in Table 4 along with outcomes seen for other lifeprolonging therapies in this disease.
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Ongoing issues Mechanisms of resistance to enzalutamide are under investigation and their discovery is of great clinical relevance because almost all patients eventually progress on therapy. Postulated mechanisms of de novo resistance include the presence of AR splice variants, which, as mentioned earlier, are truncated forms of the AR protein lacking the C-terminal ligand–binding domain and thought to be constitutively active [8,9]. Enzalutamide may be ineffective in these patients because its mechanism of action involves binding the AR C-terminal, although it remains unclear whether these splice variants (in particular AR v7) are truly predictive of AR antagonist resistance or are merely markers of more aggressive disease with worsened prognosis [8,9]. Several assays to determine the presence of this biomarker are undergoing further validation in prospective trials [32]. Reciprocal feedback between the PI3K and AR signaling pathways has also been implicated [13]. Acquired resistance can be mediated through acquisition of the F876L mutation, which transforms enzalutamide into a functional AR agonist or through up-regulation and activation of the glucocorticoid receptor that can coopt AR signaling and bypass the need for activation of AR itself. Strategies are under development to confirm and overcome these and other resistance mechanisms and are discussed elsewhere [33]. Seizures were an early concern in the development of enzalutamide. As an inhibitor of the gamma-aminobutyric acid–gated chloride channel, it caused seizures at supratherapeutic doses in mice as well as in 3 patients from the initial phase I/II study at doses above the licensed 160 mg/d [25,34]. Because of this, men with with a history of seizure or a condition that could predispose to seizure, such as brain metastases, transient ischemic attack within the past year, and loss of consciousness within the past year, were excluded from the phase III AFFIRM and PREVAIL trials [28,31]. Across these 2 studies, 6 (0.4%) of the 1,672 patients treated with enzalutamide experienced a seizure. There was no statistically significant difference in incidence compared with placebo (1 of 1,244 patients). In the
Fig. 3. PSA waterfall plots from the phase I–II study showing degree of PSA level decline in patients who were chemotherapy naïve (left side) and who had received prior chemotherapy (right side). (Reproduced with permission from Scher et al [25].)
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Fig. 4. Kaplan-Maier curves demonstrating radiographic progression-free and overall survival for enzalutamide vs. placebo in the phase III postchemotherapy AFFIRM (A and B) and prechemotherapy PREVAIL (C and D) trials. (Reproduced with permission from Scher et al [28] and Beer et al [31].)
prechemotherapy PREVAIL trial, only 1 seizure occurred in the enzalutamide arm, which is reassuring given that this is the more common setting of use in contemporary clinical practice. The FDA label states that “the safety of
enzalutamide in patients with predisposing factors for seizures is unknown.” An ongoing single-arm open-label study is assessing seizure frequency in men with CRPC on enzalutamide who have risk factor(s) for seizure such as history of
Table 2 Efficacy measures for enzalutamide vs. placebo by disease manifestation in the phase III AFFIRM clinical trial conducted in postchemotherapy CRPC [28,29] Enzalutamide (n = 800)
Placebo (n = 399)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
54% 8.3 Months
2%, P o 0.001 3.0 Months, P o 0.001
Soft tissue Radiographic response (RECIST)
29%
4%, P o 0.001
Bone Incidence of any SREa Median time to first SREa
36% 17 Months
40% 13 Months, P o 0.001
Median radiographic PFS (includes bone and soft tissue)
8.3 Months
2.9 Months, Po0.001
Quality of life Improvement in HRQOL Median time to deterioration in HRQOL
42% 9.0 Months
15%, P o 0.001 3.7 Months, P o 0.001
Overall survival Median overall survival
18.4 Months
13.6 Months, P o 0.001
b
HRQOL ¼ health-related quality of life; SRE ¼ skeletal-related event. a SRE defined as need for radiotherapy or surgery to bone, need for change of antineoplastic therapy due to bone pain, clinically apparent pathologic bone fracture, or spinal cord compression. b HRQOL was measured using the FACT-P score.
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Table 3 Efficacy measures for enzalutamide vs. placebo by disease manifestation in the phase III PREVAIL clinical trial conducted in patients with CRPC before chemotherapy [31] Enzalutamide (n ¼ 872)
Placebo (n ¼ 845)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
78% 11.2 Months
3%, P o 0.001 2.8 Months, P o 0.001
Soft tissue Radiographic response (RECIST)
59%
5%, P o 0.001
Bone Incidence of any SRE Median time to first SRE
32% 31.1 Months
37%, P o 0.001 31.3 Months
Median radiographic PFS (includes bone and soft tissue)
Not reached
3.9 Months, P o 0.001
Quality of life Median time to HRQOL declinea
11.3 Months
5.6 Months, P o 0.001
Overall survival Median overall survival (estimated)
32.4 Months
30.2 Months, P o 0.001
HRQOL ¼ health-related quality of life; SRE ¼ skeletal-related event. a HRQOL was measured using the FACT-P score.
prior seizure, cerebrovascular accident/transient ischemic attack, or treated brain metastases (NCT01977651). Intense efforts are ongoing to determine whether enzalutamide is best used in combination or in sequence with other agents to maximize outcome for the individual patient. One such study is comparing the safety and efficacy of enzalutamide alone with enzalutamide plus abiraterone as first-line therapy for chemotherapy-naïve CRPC in a multicentre Alliance phase III trial that is planning to enroll 1,224 patients and has a primary end point of overall survival (NCT01949337). Trials have also been designed to test whether it is better to continue a drug on which a patient is progressing and add another drug or whether the first should be discontinued before the second is started. Equally important are trials in earlier disease states (Table 5) including studies combining enzalutamide with radiotherapy (both with and without ADT) as definitive treatment for high-risk localized prostate cancer based on preclinical studies from the Sawyer's group showing that AR signaling contributes to activation of DNA-repair pathways, which could increase resistance to radiation therapy (NCT02064582 and NCT02028988) [35]. Also important are studies of enzalutamide monotherapy without concomitant androgen lowering therapies: a study in 67 men with
treatment-naïve castration-sensitive prostate cancer showed 490% of patients achieving deep and durable PSA level declines [36]. This approach has the potential to minimize the adverse events associated with conventional ADT and improve overall quality of life. Enzalutamide is also being compared with bicalutamide as first-line treatment for castration-sensitive metastatic prostate cancer in combination with ADT (NCT02058706). Finally, the drug has shown activity in triple-negative breast cancer, which has opened up a whole new area of development (NCT01597193 and NCT02007512).
Conclusion The story of enzalutamide illustrates how understanding the biology of treatment resistance can be used to rationally design therapeutic compounds with subsequent clinical benefit for patients. As a potent AR signaling inhibitor that can be safely administered to patients, enzalutamide has revolutionized the treatment of metastatic CRPC. It is now being explored in other prostate cancer disease states as well as in other cancers. Understanding the mechanisms of resistance to this agent may help better define the exact
Table 4 Efficacy measures of novel therapies in the first-line treatment of CRPC described by disease manifestation
Enzalutamide (PREVAIL) [28,29] Abiraterone (COU-AA-302) [37,38] Docetaxel (TAX 327)[22] Bicalutamide [17,18]
PSA response rate (450% decline)
Radiographic soft tissue response rate (RECIST)
Median PFS (radiographic)
HRQOL (median time to deterioration of FACT-P score)
78% 62% 48% 23%
59% 36% 12% 0%
Not reached 16.5 Months 15.1 Months 4 Months
11.3 Months 12.7 Months NR NR
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Table 5 Ongoing studies of enzalutamide in earlier disease states Disease state Localized (neoadjuvant)
Trial design
Randomized phase II; high/ intermediate risk Localized (concurrent RT) Single-arm phase II; intermediate risk Localized (concurrent RT) Single-arm phase II; high risk Localized (adjuvant) Single-arm phase II; high risk— postprostatectomy Rising PSA level (concurrent Randomized phase II; biochemical salvage RT) recurrence postprostatectomy Rising PSA (first-line systemic tx. Randomized phase III; for castration-sensitive disease) biochemical recurrence postprostatectomy or RT; PSA doubling time o9 months. Castrate-sensitive metastatic Randomized phase II disease Castrate-sensitive metastatic Multiarm randomized phase III disease Rising PSA level (castrate Randomized phase III; PSA resistant) doubling time o10 months
Intervention
Primary end point
NCT number
6 Months neoadj. ADT þ abiraterone ⫾ Enza RT þ Enza 6 months
Pathologic response rate
02268175
PSA level at 6 months
02028988
Safety and tolerability Biochemical recurrence rate 2-Year rate of undetectable PSA Metastasis-free survival
02064582 01927627
RT þ ADT þ Enza 6 months Adjuvant Enza 2 years Salvage RT ⫾ Enza 6 months ADT vs. ADT/Enza vs. Enza alone
02203695 02319837
ADT/Enza vs. ADT/Bicalutamide PSA response rate
02058706
ADT ⫾ Enza (with multiple other Overall survival comparator arms) Enza vs. placebo Metastasis-free survival
00268476 (STAMPEDE) 02003924 (PROSPER)
RT = radiation therapy.
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R.M. Bambury, H.I. Scher / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–9 [22] Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12. [23] Machiels JP, Mazzeo F, Clausse M, Filleul B, Marcelis L, Honhon B, et al. Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer. J Clin Oncol 2008;26:5261–8. [24] Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324:787–90. [25] Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437–46. [26] Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148–59. [27] Scher HI, Morris MJ, Basch E, Heller G. End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol 2011;29:3695–704. [28] Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–97. [29] Fizazi K, Scher HI, Miller K, Basch E, Sternberg CN, Cella D, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014;15: 1147–56. [30] Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy—Prostate: results from a clinical trial of patients
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with metastatic hormone-refractory prostate cancer. Value Health 2009;12:124–9. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424–33. Bambury RM, Louw J, Krupa R, Danila D, Arslan Z, Schreiber NA, et al. Characteristics of de novo resistance to androgen targeted therapies through circulating tumors cells analysis in metastatic castration resistant prostate cancer patients. In: ESMO. Madrid, Spain; 2014. Bastos DA, Dzik C, Rathkopf D, Scher HI. Expanding androgen- and androgen receptor signaling-directed therapies for castration-resistant prostate cancer. Oncology (Williston Park) 2014;28:693–9. Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, et al. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. Prostate 2011;71:480–8. Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 2013;3:1245–53. Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, et al. Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol 2014;15:592–600. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138–48. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castrationresistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16:152–60.
Seminar article
Enzalutamide: Development from bench to bedside R.M. Bambury*, H.I. Scher New York, NY Received 15 December 2014; accepted 31 December 2014
Abstract Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 60 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First-generation compounds such as bicalutamide had only modest efficacy. Furthermore, in the setting of AR overexpression or specific mutations in the AR ligand– binding domain, these early compounds had partial agonist properties and induced disease progression. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types. r 2015 Elsevier Inc. All rights reserved.
Keywords: Enzalutamide; Prostate cancer; MDV3100
Introduction Prostate tissue, both benign and malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation [1]. The therapeutic benefit of targeting this pathway has been apparent since 1941, when Huggins and Hodges [2] reported that reducing androgen levels through surgical castration or exogenous estrogen administration decreased prostate cancer proliferation (as measured by serum acid phosphatase levels) and that exogenous testosterone increased its activity. Palliation of symptoms was also documented in the primary and distant sites [3]. Later, the demonstration in the 1980s that gonadotrophinreleasing hormone analogues produce a medical castration and allow patients to avoid surgical orchiectomy, positioned these compounds as the first-line standard of care for the management of advanced disease: a strategy termed androgen deprivation therapy (ADT) [4]. The biology of prostate cancers progressing on ADT (i.e., castration-resistant prostate cancer [CRPC]) is notable for a number of features that contribute to continued AR Corresponding author. Tel.: þ1-917-355-3984. E-mail address: [email protected] (R.M. Bambury). *
http://dx.doi.org/10.1016/j.urolonc.2014.12.017 1078-1439/r 2015 Elsevier Inc. All rights reserved.
signaling despite castrate levels of serum testosterone (o50 ng/dl). These tumors harbor amplification of the AR gene in 30% of cases and activating AR point mutations in others (the specific types and frequency vary across reports) [5,6]. AR protein is expressed at higher levels in CRPC relative to benign prostate tissue and treatment-naïve prostate cancer [7]. AR splice variants, truncated forms of the AR protein lacking the C-terminal ligand-binding domain, can also emerge, which can activate signaling in the absence of the ligand [8,9]. Furthermore, CRPC can evolve mechanisms that result in high intratumoral androgen levels despite serum levels in the castrate range. Contributing to the high levels are continued production of androgens in the adrenal glands, increased tumor uptake of available circulating androgens, and up-regulation of the androgen biosynthetic machinery in the tumor itself [10,11]. Reciprocal feedback between the AR and mammalian target of rapamycin pathways, the latter altered in upwards of 70% of CRPC cases, also contributes to resistance [12,13]. These and other molecular alterations can sensitize the tumor to lower levels of circulating androgens or enable growth independent of them. The result is that, in most of the cases, CRPC remains dependent on AR signaling. Clinical evidence of this
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includes that the overwhelming majority of CRPCs continue to secrete prostate-specific antigen (PSA), an AR response gene, and that continuation of ADT in CRPC improves median overall survival by 2 to 6 months [14]. First-generation AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the AR molecule. Beginning in the 1970s, a succession of the molecules were developed including cyproterone acetate, flutamide, bicalutamide, and nilutamide, each with activity as single agents in the non–castrate disease setting. Subsequently, each was evaluated in combination with standard ADT (orchiectomy or gonadotrophin-releasing hormone agonist/antagonist therapy) and was ultimately shown to provide, at best, modest improvements in overall outcomes relative to ADT alone [15]. Their effects in CRPC were also modest, with Z50% PSA decline seen in only 25% of cases and few objective tumor regressions [16–18]. Nevertheless, these agents provided further proof that AR signaling could be targeted in CRPC, although more potent molecules were needed, especially given the evidence that over time, they could become agonists, as evidenced by the observation of withdrawal responses when they were discontinued [19]. This was subsequently shown in laboratory models to occur because these agents become agonists in the setting of AR overexpression [20]. The focus of clinical investigation then shifted toward the development of cytotoxic agents, and in 1996, the first cytotoxic—mitoxantrone—was shown to provide palliation of the symptoms in CRPC [21]. This was followed shortly thereafter by tubulin-targeting agents, and in 2004, docetaxel was Food and Drug Administration (FDA) approved based on a survival benefit in 2 landmark phase 3 trials [22,23]. The focus of clinical development in CRPC then shifted to the predocetaxel and postdocetaxel spaces, and the central belief at the time was that these tumors were “hormone refractory” and that there was no role for “hormonal agents” in this disease state. However, some investigators maintained an interest in identifying new and more potent AR signaling blockade strategies and in particular, next-generation antiandrogens with greater AR binding affinity and without agonist effects in tumors with overexpressed AR [20].
Enzalutamide discovery and development Preclinical discovery The effort to develop such a compound began with an experiment whereby a series of 7 matched pre-ADT castration-sensitive and post-ADT castration-resistant prostate cancer cell lines were profiled to identify differences in gene expression [20]. Notable here was that mRNA studies showed that AR was the only gene consistently overexpressed in all 7 lines. Subsequently, Sawyers and Jung used derivatives of the nonsteroidal thiohydantoin AR agonist
RU59063, selected for its high affinity and selectivity for AR over other steroid receptors, in a screen for activity against LNCaP-AR cells with overexpressed AR protein [24]. Nearly 200 derivatives of the compound were synthesized and screened for their ability to inhibit growth and PSA secretion, of which RD162, which was later modified to become MDV3100, was chosen for further study based on oral bioavailability and longer serum halflife. Xenograft studies were performed, which showed that both the compounds had significant antitumor effects in CRPC mouse models with overexpressed AR. Bicalutamide had little or no inhibitory effects in these models, and in some cases, it showed agonist effects. Mechanistically, both enzalutamide and bicalutamide bind AR at its ligandbinding domain to prevent signaling; however, enzalutamide has 4-fold greater binding affinity than bicalutamide and, unique from bicalutamide, inhibits AR translocation to the nucleus and inhibits binding of the ligand-bound receptor complex to DNA (Fig. 1) [24]. Enzalutamide is also active against prostate cancer cell lines bearing the W741C AR point mutation that is known to confer resistance to bicalutamide [24]. Clinical testing Phase I/II clinical trial The first-in-human study of enzalutamide enrolled 140 men with metastatic CRPC across 5 US centers from July 2007 to December 2008 [25]. Importantly, this and subsequent trials incorporated the Prostate Cancer Working Group 2 (PCWG2) recommendations for evaluating systemic treatment approaches in CRPC [26]. The recommendations are based on several key principles: abandon grouped categorizations of response that consider all sites of disease together in favor of reporting outcomes for each manifestation of disease independently (e.g., changes in PSA levels, osseous disease, soft tissue nodal, or visceral disease); when evaluating bone scans, interpret apparent worsening with apparent new lesions on a first follow-up scan carefully by requiring the documentation of new lesions on a second follow-up before considering a patient to have progressed (in the absence of other signs of progression); ensure a drug is no longer working before stopping therapy; and continue treatment despite signs of progression (e.g., slow rises in PSA levels) that are not clinically meaningful. The trial was initially designed as a single-arm phase I study to assess safety, tolerability, and maximum-tolerated dose using a 3 þ 3 rule. However, when PSA level declines were observed in all the first 6 patients, the trial was modified and expanded in both prechemotherapy and postchemotherapy cohorts using a phase I to II design to allow a more robust assessment of treatment efficacy. Doses ranging from 30 to 600 mg/d were tested, and the most common treatment-related grade 3 to 4 adverse events were fatigue (11%) and arthralgia (2%). Seizures were observed
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Fig. 1. Pharmacodynamic effects of enzalutamide and bicalutamide on AR signaling in the setting of AR protein overexpression. Binding affinity of dihydrotestosterone (DHT) is included for comparison. (Reproduced with permission from Yu Chen.)
in 3 (2%) patients, all of whom received doses more than 360 mg daily. Overall, the incidence of these adverse events was increased at doses above 240 mg/d, and there were no seizures recorded at or below this dose level, so it was defined as the maximum-tolerated dose. To illustrate the on-target pharmacodynamic activity of enzalutamide, measurement of androgen to AR binding using F-fluoro-5alpha-dihydrotestosterone (FDHT)-positron emission tomography scans was performed to measure uptake of radiolabeled dihydrotestosterone (FDHT) in 22 patients (Fig. 2). There was a significant decrease in metastatic uptake at all dose levels, demonstrating that enzalutamide was successfully blocking dihydrotestosterone binding to AR and illustrating the on-target effects of the drug. The extent of reduction in FDHT uptake appeared to plateau at a dose of 150 mg/d despite that higher plasma concentrations of drug were seen with higher dose levels. A secondary objective of the study was to assess antitumor activity (Table 1). By manifestation, PSA level decline of Z50% was seen in 61% of chemotherapy-naïve patients and 52% of patients who had received prior chemotherapy (Fig. 3). The declines were seen at all dose levels with a plateau in the degree of decline at 240 mg/d. The importance of the PCWG2 recommendation to not stop therapy based on PSA level changes alone is illustrated by a patient who was continued on treatment with enzalutamide for 3.5 years in the setting of a slowly rising PSA level without radiographic or clinical progression [27]. Circulating tumor cell (CTC, CellSearch) enumeration was
performed at baseline and monthly as a measure of a direct effect of drug on the tumor because of concerns that PSA level declines might merely be owing to blockade of AR signaling independent of an effect on tumor growth. Conversion from unfavorable counts of Z5 CTCs/7.5 ml to favorable counts of 4 or fewer CTCs/7.5 ml was seen in 49% of 51 measurable patients. There was also a 22% partial response rate in soft tissue lesions (the RECIST criteria). Overall, response rates were higher in chemotherapy-naïve patients relative to those who had received prior chemotherapy (Table 1). A dose of 160 mg/d was selected for phase III testing because it appeared to have similar activity to that of higher doses based on FDHT-positron emission tomography, PSA level, and conventional imaging studies and was associated with lower toxicity. Phase III clinical trials The first registration phase III clinical trial (AFFIRM) testing enzalutamide was conducted between September 2009 and November 2010 at 156 sites across 5 countries [28]. A total of 1,199 men with progressive, metastatic CRPC (as per the PCWG2 criteria) who had received prior docetaxel were randomized 2:1 to receive enzalutamide 160 mg/d or placebo. The use of an AR-targeted therapy in the postchemotherapy setting was a paradigm shift when compared with where these agents had typically been used in the past. An independent data safety monitoring committee unblinded the study in November 2011 when a planned
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Fig. 2. FDHT-PET before enzalutamide and after enzalutamide administration in a patient with widespread vertebral bone metastases. PET ¼ positron emission tomography. (Reproduced with permission from Scher et al [25].) (Color version of figure is available online.)
interim analysis showed that enzalutamide was associated with a significant overall survival benefit (hazard ratio for death ¼ 0.63; P ¼ 0.001) (Fig. 4B). Enzalutamide was associated with clinically and statistically significant improvements in PSA response rate (Z50% decline in 54% vs. 2%, P o 0.01), median radiographic progressionfree survival (8.3 vs. 3.0 mo, P o 0.01), and median overall survival (18.4 vs. 13.6 mo, P o 0.01) (Fig. 4A and B and Table 2). Enzalutamide was generally well tolerated, although there was increased incidence of hot flashes (20% vs. 10%), musculoskeletal pain (14% vs. 10%), and headaches (12% vs. 6%) when compared with placebo. Seizures occurred in 5 of 800 patients treated with enzalutamide. Based on these findings, in an expedited review process, the FDA approved enzalutamide for use in patients with CRPC who had received prior chemotherapy in August 2012—less than 2 years after the last patient was enrolled on AFFIRM. A recent update of this trial also demonstrated
that enzalutamide also prolonged median time to first skeletal-related event (13 vs. 17 mo, P ¼ 0.0001, Table 2) [29]. The same update also showed that enzalutamide improved health-related quality of life in 42% of patients when compared with 15% on placebo (P o 0.0001) when measured using the FACT-P score (Table 2) [29]. This validated tool measures quality of life in patients with prostate cancer across 5 domains: physical well-being, functional well-being, social well-being, emotional well-being, and a prostate cancer subscale that measures symptoms such as fatigue and pain [30]. Enzalutamide led to a statistically significant improvement in all the 5 domains when compared with placebo [29]. A prechemotherapy phase III trial followed (PREVAIL), in which enzalutamide was compared with placebo in men with metastatic CRPC who had not received prior cytotoxic chemotherapy [31]. A larger sample size was needed to demonstrate improved overall survival because of the multiple life-prolonging therapies that had become available
R.M. Bambury, H.I. Scher / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–9 Table 1 Efficacy measures for enzalutamide described by disease manifestation (as described by PCWG2) in the initial phase I/II clinical trial No prior chemotherapy (n ¼ 65)
Prior chemotherapy (n ¼ 75)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
62% 41 Weeks
51% (P ¼ 0.23) 21 Weeks (P ¼ 0.01)
Soft tissue Radiographic response (RECIST)
36%
12%
Bone Bone scan stable at 12 weeks 63%
51%
Radiographic PFS (median)
Not reached
29 Weeks (P ¼ 0.01)a
PFS ¼ progression-free survival. a P values refer to comparison between the no prior chemotherapy vs. prior chemotherapy cohorts.
for this disease. Patients were likely to receive some or all of these after progression on protocol-defined therapy, with subsequent dilution of the effect of enzalutamide on the overall survival. In total, 1,717 men were enrolled between September 2010 and September 2012, of whom 485% had received prior antiandrogens such as bicalutamide or nilutamide. After a median follow-up of 22 months, there were again substantial improvements in the proportion of patients achieving a Z50% PSA level decline (78% vs. 3%), median radiographic progression-free survival (not reached vs. 3.9 mo), and median overall survival (not reached vs. 31.0 mo, P o 0.001) (Fig. 4B and C and Table 3). Median time to initiation of chemotherapy was 28 months with enzalutamide vs. 11 months with placebo (P o 0.001) (Table 3). Based on these data, in September 2014, the FDA expanded the indication for enzalutamide to patients with metastatic CRPC regardless of prior therapies. The efficacy outcomes seen with enzalutamide for first-line treatment of metastatic CRPC are listed in Table 4 along with outcomes seen for other lifeprolonging therapies in this disease.
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Ongoing issues Mechanisms of resistance to enzalutamide are under investigation and their discovery is of great clinical relevance because almost all patients eventually progress on therapy. Postulated mechanisms of de novo resistance include the presence of AR splice variants, which, as mentioned earlier, are truncated forms of the AR protein lacking the C-terminal ligand–binding domain and thought to be constitutively active [8,9]. Enzalutamide may be ineffective in these patients because its mechanism of action involves binding the AR C-terminal, although it remains unclear whether these splice variants (in particular AR v7) are truly predictive of AR antagonist resistance or are merely markers of more aggressive disease with worsened prognosis [8,9]. Several assays to determine the presence of this biomarker are undergoing further validation in prospective trials [32]. Reciprocal feedback between the PI3K and AR signaling pathways has also been implicated [13]. Acquired resistance can be mediated through acquisition of the F876L mutation, which transforms enzalutamide into a functional AR agonist or through up-regulation and activation of the glucocorticoid receptor that can coopt AR signaling and bypass the need for activation of AR itself. Strategies are under development to confirm and overcome these and other resistance mechanisms and are discussed elsewhere [33]. Seizures were an early concern in the development of enzalutamide. As an inhibitor of the gamma-aminobutyric acid–gated chloride channel, it caused seizures at supratherapeutic doses in mice as well as in 3 patients from the initial phase I/II study at doses above the licensed 160 mg/d [25,34]. Because of this, men with with a history of seizure or a condition that could predispose to seizure, such as brain metastases, transient ischemic attack within the past year, and loss of consciousness within the past year, were excluded from the phase III AFFIRM and PREVAIL trials [28,31]. Across these 2 studies, 6 (0.4%) of the 1,672 patients treated with enzalutamide experienced a seizure. There was no statistically significant difference in incidence compared with placebo (1 of 1,244 patients). In the
Fig. 3. PSA waterfall plots from the phase I–II study showing degree of PSA level decline in patients who were chemotherapy naïve (left side) and who had received prior chemotherapy (right side). (Reproduced with permission from Scher et al [25].)
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Fig. 4. Kaplan-Maier curves demonstrating radiographic progression-free and overall survival for enzalutamide vs. placebo in the phase III postchemotherapy AFFIRM (A and B) and prechemotherapy PREVAIL (C and D) trials. (Reproduced with permission from Scher et al [28] and Beer et al [31].)
prechemotherapy PREVAIL trial, only 1 seizure occurred in the enzalutamide arm, which is reassuring given that this is the more common setting of use in contemporary clinical practice. The FDA label states that “the safety of
enzalutamide in patients with predisposing factors for seizures is unknown.” An ongoing single-arm open-label study is assessing seizure frequency in men with CRPC on enzalutamide who have risk factor(s) for seizure such as history of
Table 2 Efficacy measures for enzalutamide vs. placebo by disease manifestation in the phase III AFFIRM clinical trial conducted in postchemotherapy CRPC [28,29] Enzalutamide (n = 800)
Placebo (n = 399)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
54% 8.3 Months
2%, P o 0.001 3.0 Months, P o 0.001
Soft tissue Radiographic response (RECIST)
29%
4%, P o 0.001
Bone Incidence of any SREa Median time to first SREa
36% 17 Months
40% 13 Months, P o 0.001
Median radiographic PFS (includes bone and soft tissue)
8.3 Months
2.9 Months, Po0.001
Quality of life Improvement in HRQOL Median time to deterioration in HRQOL
42% 9.0 Months
15%, P o 0.001 3.7 Months, P o 0.001
Overall survival Median overall survival
18.4 Months
13.6 Months, P o 0.001
b
HRQOL ¼ health-related quality of life; SRE ¼ skeletal-related event. a SRE defined as need for radiotherapy or surgery to bone, need for change of antineoplastic therapy due to bone pain, clinically apparent pathologic bone fracture, or spinal cord compression. b HRQOL was measured using the FACT-P score.
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Table 3 Efficacy measures for enzalutamide vs. placebo by disease manifestation in the phase III PREVAIL clinical trial conducted in patients with CRPC before chemotherapy [31] Enzalutamide (n ¼ 872)
Placebo (n ¼ 845)
PSA Response (450% decline) Time to PSA progression (425% increase from nadir)
78% 11.2 Months
3%, P o 0.001 2.8 Months, P o 0.001
Soft tissue Radiographic response (RECIST)
59%
5%, P o 0.001
Bone Incidence of any SRE Median time to first SRE
32% 31.1 Months
37%, P o 0.001 31.3 Months
Median radiographic PFS (includes bone and soft tissue)
Not reached
3.9 Months, P o 0.001
Quality of life Median time to HRQOL declinea
11.3 Months
5.6 Months, P o 0.001
Overall survival Median overall survival (estimated)
32.4 Months
30.2 Months, P o 0.001
HRQOL ¼ health-related quality of life; SRE ¼ skeletal-related event. a HRQOL was measured using the FACT-P score.
prior seizure, cerebrovascular accident/transient ischemic attack, or treated brain metastases (NCT01977651). Intense efforts are ongoing to determine whether enzalutamide is best used in combination or in sequence with other agents to maximize outcome for the individual patient. One such study is comparing the safety and efficacy of enzalutamide alone with enzalutamide plus abiraterone as first-line therapy for chemotherapy-naïve CRPC in a multicentre Alliance phase III trial that is planning to enroll 1,224 patients and has a primary end point of overall survival (NCT01949337). Trials have also been designed to test whether it is better to continue a drug on which a patient is progressing and add another drug or whether the first should be discontinued before the second is started. Equally important are trials in earlier disease states (Table 5) including studies combining enzalutamide with radiotherapy (both with and without ADT) as definitive treatment for high-risk localized prostate cancer based on preclinical studies from the Sawyer's group showing that AR signaling contributes to activation of DNA-repair pathways, which could increase resistance to radiation therapy (NCT02064582 and NCT02028988) [35]. Also important are studies of enzalutamide monotherapy without concomitant androgen lowering therapies: a study in 67 men with
treatment-naïve castration-sensitive prostate cancer showed 490% of patients achieving deep and durable PSA level declines [36]. This approach has the potential to minimize the adverse events associated with conventional ADT and improve overall quality of life. Enzalutamide is also being compared with bicalutamide as first-line treatment for castration-sensitive metastatic prostate cancer in combination with ADT (NCT02058706). Finally, the drug has shown activity in triple-negative breast cancer, which has opened up a whole new area of development (NCT01597193 and NCT02007512).
Conclusion The story of enzalutamide illustrates how understanding the biology of treatment resistance can be used to rationally design therapeutic compounds with subsequent clinical benefit for patients. As a potent AR signaling inhibitor that can be safely administered to patients, enzalutamide has revolutionized the treatment of metastatic CRPC. It is now being explored in other prostate cancer disease states as well as in other cancers. Understanding the mechanisms of resistance to this agent may help better define the exact
Table 4 Efficacy measures of novel therapies in the first-line treatment of CRPC described by disease manifestation
Enzalutamide (PREVAIL) [28,29] Abiraterone (COU-AA-302) [37,38] Docetaxel (TAX 327)[22] Bicalutamide [17,18]
PSA response rate (450% decline)
Radiographic soft tissue response rate (RECIST)
Median PFS (radiographic)
HRQOL (median time to deterioration of FACT-P score)
78% 62% 48% 23%
59% 36% 12% 0%
Not reached 16.5 Months 15.1 Months 4 Months
11.3 Months 12.7 Months NR NR
R.M. Bambury, H.I. Scher / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–9
8
Table 5 Ongoing studies of enzalutamide in earlier disease states Disease state Localized (neoadjuvant)
Trial design
Randomized phase II; high/ intermediate risk Localized (concurrent RT) Single-arm phase II; intermediate risk Localized (concurrent RT) Single-arm phase II; high risk Localized (adjuvant) Single-arm phase II; high risk— postprostatectomy Rising PSA level (concurrent Randomized phase II; biochemical salvage RT) recurrence postprostatectomy Rising PSA (first-line systemic tx. Randomized phase III; for castration-sensitive disease) biochemical recurrence postprostatectomy or RT; PSA doubling time o9 months. Castrate-sensitive metastatic Randomized phase II disease Castrate-sensitive metastatic Multiarm randomized phase III disease Rising PSA level (castrate Randomized phase III; PSA resistant) doubling time o10 months
Intervention
Primary end point
NCT number
6 Months neoadj. ADT þ abiraterone ⫾ Enza RT þ Enza 6 months
Pathologic response rate
02268175
PSA level at 6 months
02028988
Safety and tolerability Biochemical recurrence rate 2-Year rate of undetectable PSA Metastasis-free survival
02064582 01927627
RT þ ADT þ Enza 6 months Adjuvant Enza 2 years Salvage RT ⫾ Enza 6 months ADT vs. ADT/Enza vs. Enza alone
02203695 02319837
ADT/Enza vs. ADT/Bicalutamide PSA response rate
02058706
ADT ⫾ Enza (with multiple other Overall survival comparator arms) Enza vs. placebo Metastasis-free survival
00268476 (STAMPEDE) 02003924 (PROSPER)
RT = radiation therapy.
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