Enzalutamide for treatment of CRPC: Rationale for sequencing and potential clinical biomarker for resistance

Abstract

The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). Enzalutamide is a potent AR antagonist that was initially approved in 2012 for men with CRPC who had previously failed chemotherapy treatment with docetaxel. Herein, we reviewed 2 key manuscripts that have recently appeared in the New England Journal of Medicine regarding enzalutamide. The PREVAIL Phase 3 trial was designed to evaluate enzalutamide before chemotherapy in men with CRPC. The study illustrated that 65% of patients receiving enzalutamide had radiographic-progression free survival. There was a significant risk reduction of radiographic progression or death, compared with the placebo group. The enzalutamide group's median overall survival was 32.4 months vs. 30.2 months in the placebo group.

Keywords:

• Androgen receptor
• hormonal therapy
• prostate cancer
• resistance
• splice-variants
• testosterone

The second paper, by Antonarakis and colleagues, investigated the hypothesis that androgen receptor splice variant 7 (AR-V7) may play a role in both primary and acquired resistance to enzalutamide and abiraterone. Twenty-eight percent of patients in this trial were AR-V7 positive; PSA progression-free survival and clinical/radiographic progression-free survival were significantly worse in this cohort. This study showed a strong association between the presence of AR-V7 in circulating tumor cells and resistance to enzalutamide and abiraterone, however it did not prove a causal role for AR-V7.

Prostate cancer is the most common cancer among men in the United States, and accounts for more cancer-specific deaths in men than any cancer, with the exception of lung cancer. Androgen ablation (either surgical or medical) is the cornerstone of treatment for men with metastatic disease. Ultimately, most of these men will develop castration-resistant prostate cancer (CRPC) warranting additional lines of therapy. Sawyers and colleagues demonstrated that prostate cancer cells from tumors that progress on androgen ablation still continue to express the androgen receptor (AR) and are dependent on signaling through the receptor.¹ This seminal observation has resulted in a second generation of androgen-targeted therapies for CRPC. Enzalutamide is one such agent that was developed as a potent AR antagonist (5-fold greater binding affinity compared to bicalutamide). Enzalutamide was initially approved by the Food and Drug Administration in August 2012 for men with CRPC who had previously failed chemotherapy treatment with docetaxel.²

Herein, we will review 2 key manuscripts that have recently appeared in the New England Journal of Medicine regarding enzalutamide; “Metastatic Prostate Cancer before Chemotherapy,” and, “AR-47 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer.”^3,4 The first article published the data from a double-blind phase 3 study with patients whom had developed CRPC and had not received chemotherapy despite progression after androgen deprivation therapy. Enzalutamide has previously been shown to significantly increase overall-survival and progression-free survival in CRPC patients with progression after chemotherapy. Also reported were delays in skeletal-related events in those receiving enzalutamide.²

This PREVAIL Phase 3 trial was designed to evaluate enzalutamide before chemotherapy in men with CRPC. The study enrolled 1,717 patients to receive either enzalutamide (dose 160mg) or placebo once daily. Tomography or magnetic resonance imaging (MRI), in addition to bone scanning, were used to determine the co-primary endpoint, alongside overall survival, of radiographic-progression free survival, with imaging at weeks 9, 17, 25, and every 12 weeks thereafter. The secondary endpoints in the study were the time until cytotoxic chemotherapy commenced, time until first skeletal-related event, response of soft tissue, prostate-specific antigen (PSA) progression after administration of endocrine therapy, and a decline of PSA level of 50% or more from baseline.

The study was stopped after 765 deaths were reported, or 67% of patients. The enzalutamide group had a total of 872 patients enrolled and the placebo had 845. Enzalutamide was administered for a total 16.6 months vs. 4.6 months for the placebo group. After a 12 month-follow up the enzalutamide group had 65% of patients with radiographic-progression free survival vs. 14% of patients in placebo group. There was an 81% significant risk reduction of radiographic progression or death (hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0 .001). 118 of 832 patients in the enzalutamide group [14%] vs. 321 of 801 patients in the placebo group [40%] had an outcome of radiographic progression or death.

The enzalutamide group resulted in fewer deaths then the placebo group (241 of 872 patients [28%] vs. 299 of 845 patients [35%]). Overall there was a 29% decrease in the risk of death for the enzalutamide group compared with the placebo group (hazard ratio 0.71; 95% CI, 0.60 to 0.84; P < 0 .001). The enzalutamide group's median overall survival was 32.4 months vs. 30.2 months in the placebo group. Review of the interim analysis resulted in the halting of the trial and made those on the placebo arm eligible to receive enzalutamide.

It is important to note that 40% of patients in the enzalutamide group subsequently received antineoplastic therapy as compared to 70% of those in the placebo group. Subsequent therapies were docetaxel, administered to 33% of enzalutamide patients and 57% of placebo patients, and abiraterone, received by 21% and 46%, respectively. Adverse events due to enzalutamide included fatigue, back pain, constipation and arthralgia. Also, hot flush, hypertension and falls were higher for the enzalutamide group compared to the placebo group. The most common grade 3 or higher adverse event was hypertension. In conclusion, the PREVAIL trial showed enzalutamide reduced the risk of radiographic progression and improved survival for men with CPRC who haven't received chemotherapy. It also delayed the initiation of chemotherapy for men with metastatic prostate cancer.

Abiraterone, a cytochrome P450 17A1 inhibitor, like enzalutamide, targets deregulated AR signaling. However, approximately 20–40 percent of men with CRPC have no response, measured by PSA levels, to enzalutamide and abiraterone, and in those initially sensitive responses to these therapies have been limited.⁴ This has raised new questions about resistance development, optimization with combination therapy, and new targets that should be investigated.

AR amplification, mutation and alternative splicing have all been suggested as potential resistance mechanisms to anti-androgen treatments. Over half of CRPC patients have at least one of these aberrations in the AR pathway.⁵ In a paper published in The New England Journal of Medicine in September 2014, Antonarakis and colleagues investigated the hypothesis that androgen receptor splice variant 7 (AR-V7) may play a role in both primary and acquired resistance to enzalutamide and abiraterone.⁶

Androgen receptor splice variants, multiple of which have been discovered, encode a truncated androgen receptor protein that lacks the C-terminal ligand-binding domain. The resultant proteins are unable to bind ligand and are active transcription factors.⁶ The authors suggested that AR-V7 is the most important AR splice variant, as it is the only known variant which encodes a functional protein that is detectable in clinical specimens.⁴ The expression of AR-V7 is increased 20-fold in metastatic CRPC. Enzalutamide acts by binding to the ligand-binding domain of AR, and abiraterone is a ligand-depleting agent, as AR splice variants render AR signaling ligand-independent, it may be associated with resistance to enzalutamide and abiraterone.

Antonarakis and colleagues study included men with CRPC who were about to begin treatment with enzalutamide or abiraterone, with 31 men in each cohort. Circulating tumor cell samples were collected at baseline, at the time of response to either drug, and at the time of resistance to either drug. AR-V7 status was determined by mRNA detection using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays. Importantly, in all patients with detectable AR-V7, full-length androgen receptor mRNA was also expressed and at higher levels than AR-V7 (with one exception). Outcomes were PSA response rate (>50% PSA decline), PSA progression-free survival, clinical/radiographic progression-free survival, and overall survival.

In the enzalutamide cohort, 39% were AR-V7–positive and 61% were AR-V7–negative. Overall, about 2-third of patients had received previous abiraterone and docetaxel, and about one-third had visceral metastasis.² Of note, the percentages of patients with these characteristics were much higher among AR-V7–positive patients. Best PSA response was 0% in the AR-V7–positive patients compared with 53% in the AR-V7–negative group. PSA progression-free survival and clinical/radiographic progression-free survival were significantly better in the AR-V7–negative patients (P < .001 for both endpoints).

In the abiraterone cohort, 19% were AR-V7–positive and 81% were AR-V7–negative. Overall, only 13% had received prior enzalutamide, 16% had received prior docetaxel, and 26% had visceral metastases. Best PSA response was 0% in the AR-V7–positive patients compared with 68% in the AR-V7–negative group. As in the enzalutamide cohort, PSA progression-free survival and clinical/radiographic progression-free survival were significantly better in the AR-V7–negative group (P < .001 for both endpoints). Although prior treatment with abiraterone or enzalutamide was associated with AR-V7 positivity, AR-V7 status remained prognostic after adjustment for this factor.⁴

Among 58 evaluable patients, those who were AR-V7–positive at baseline (n = 16) remained so in subsequent samples; of the 42 men who were AR-V7–negative at baseline, 6 converted to positive status and 36 remained negative.⁴ Clinical outcomes of the “converters” were intermediate, better than those who were AR-V7–positive to begin with, but worse than those who remained AR-V7–negative.

The authors observed that in all AR-V7 positive patients, full-length AR mRNA was also expressed, and at higher levels than AR-V7. As mention above, Antonarakis and colleagues showed that PSA expression was not suppressed in AR-V7-positive patients post-treatment with enzalutamide or abiraterone. This observation is consistent with continued AR signaling despite potent inhibition of full-length AR when AR-V7 co-exists with full-length AR. In addition, when assessing the end-points of this study, the authors adjusted for the expression of full-length AR mRNA, and showed that AR-V7 status remained predictive of PSA response, as well as PSA, clinical, and radiographic progression-free survival.⁴

This study showed a strong association between the presence of AR-V7 and resistance to enzalutamide and abiraterone, however it does not prove a causal role for AR-V7. It is possible that the detection of AR-V7 might simply be a poor prognostic factor in the context of multiple therapies. Though it is unlikely that all cases of enzalutamide and abiraterone resistance will be explained by a single cause, Antonarakis and colleagues open the possibility of AR-V7 being used as a biomarker, in the future, to predict resistance to enzalutamide and abiraterone and potentially streamline treatment selection in men with CRPC, and large-scale prospective studies are required to validate this hypothesis.

Sadly, most men who develop CPRC eventually succumb to the disease. Enzalutamide offers an effective, convenient, and well-tolerated option for CRPC patients both prior to and post chemotherapy. The problem of resistance to novel anti-androgen therapies has come as a major setback in the treatment of CRPC, the elucidation of AR-V7 splice variant and the role it may play as a mechanism of resistance, and potential for its use as a resistance biomarker, offers great possibility of over-coming resistance with further research. The 2 articles published in the New England Medical Journal discussed above open our eyes to the successes and efficacies, but also the limitations, of enzalutamide in the treatment of CRPC. The PREVAIL trial showed enzalutamide to be efficacious prior to chemotherapy and this will be of particular significance to many patients who do not receive docetaxel primarily because of pre-existing medical conditions or associated toxic effects. Antonarakis et al.’s article acts as an indication for further evaluation of AR-V7 as a biomarker in larger trials, and ignites the possibilities for AR N-terminal domain inhibitors as a novel approach to overcome enzalutamide resistance.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.