Next-Generation Therapies in CRPC Take Aim at AR Resistance

Robert Dreicer, MD, MS, head of the Medical Oncology Section and deputy director at the University of Virginia Cancer Center and co-director of the Paul Mellon Urologic Oncology Center

Robert Dreicer, MD, MS

Figure. Androgen Receptor Targeting and Resistance in Prostate Cancer

As a wealth of research has shown in the past several years, therapies that target the androgen receptor (AR) pathway in patients with castration-resistant prostate cancer (CRPC) encounter complex mechanisms of resistance including the likelihood that more than 1 such signaling network is active in each individual (Figure).

Such mechanisms of resistance include AR-V7 splice variants, glucocorticoid activation of AR, gain of function mutation in dihydrotestosterone (DHT), and progesterone-responsive mutant ARs, according Robert Dreicer, MD, MS, during a presentation at New York GU^TM: 10th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies that Physicians’ Education Resource^® (PER^®) hosted March 18 in New York City. Emerging antihormonal agents for treating patients with advanced CRPC are being developed to mitigate AR resistance.

Currently, initial management of a patient with metastatic CRPC involves assessing the duration of response to androgen deprivation treatment (ADT), and then the subsequent administration of AR-directed therapy. Clinicians often choose between the AR inhibitors abiraterone acetate (Zytiga) and enzalutamide (Xtandi), and monitor patients for response to the initial agent. However, 15% to 25% of patients experience a de novo resistance to AR inhibitors. There is also clinical evidence of cross resistance with abiraterone and enzalutamide, with crossover response rates of 15% to 30%.

According to Dreicer, head of the Medical Oncology Section and deputy director at the University of Virginia Cancer Center and co-director of the Paul Mellon Urologic Oncology Center, there is a “law of thirds” with these agents, whereby approximately one-third of patients will not respond, one-third will progress after 3 to 5 months, and one-third will have a more durable response. “Clinically, we learn things pretty early,” he said.

Signals From AR-V7 Variants

Dreicer explained that clinicians will start a patient on either AR inhibitor and, if the patient does not have a durable response, then they will usually switch to docetaxel followed by the other AR inhibitor option, despite the clinician’s doubts of efficacy.AR-V7 splice variants have gained much attention in recent years. Immunohistochemistry staining has established their increased expression in patients with CRPC. It has been shown to regulate both AR-regulated genes and a unique set of genes independent from the AR, suggesting that it has an overlapping, yet distinct, role compared with full- length AR in prostate cancer cells.¹

A paper published in The New England Journal of Medicine concluded that detection of AR-V7 in the circulating tumor cells of patients with CRPC may be associated with resistance to abiraterone and enzalutamide.² In this study, 31 patients treated with enzalutamide and 31 patients treated with abiraterone were tested for AR-V7. Thirty-nine percent of the enzalutamide group and 19% of the abiraterone group had detectable AR-V7 in circulating tumor cells. For participants receiving enzalutamide or abiraterone, AR-V7—positive patients demonstrated lower prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) rates than AR-V7–negative patients. It was also found that the association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length AR.²

This attention on AR-V7 led to some missteps in researching targeted treatments for patients with this variation. One such misstep was the ARMOR3 trial (NCT02438007), which compared galeterone with enzalutamide in men with metastatic CRPC expressing AR-V7. The study was terminated because the trial’s independent data monitoring committee determined that the trial was unlikely to meet its primary endpoint of improved radio-graphic PFS.

Additional Resistance Mechanisms

“AR-V7 led overenthusiastically to looking at galeterone, which has been around for a long time, but still has a ways to go. There was a small experiment that [reported] a response to AR-V7 —positive patients, and this led to a well-designed, biomarker-driven trial, which, had it been positive, would have probably led to its regulatory approval,” Dreicer said.Findings from a study published in Cell in 2013 revealed that the glucocorticoid receptor confers resistance to antiandrogen treatments through bypassing the AR blockade.3 The investigators identified induction of the glucocorticoid receptor expression as a common feature of drug-resistant tumors and discovered that this activates a set of target genes similar to AR. Due to these factors, expression in the glucocorticoid receptor was found to be associated with clinical resistance to enzalutamide.

A mutation in the DHT could lead to CRPC, according to study results published in Cell.⁴ The gain of a function mutation in 3-beta-HSD1 leads to accumulation of prostate cancer cells. Expression of N367T accelerates the conversion of dehydroepiandrosterone to DHT in quantities large enough to activate the AR and cause CRPC. The study further concluded that 3-beta-HSD1 could be a valid target for treating patients with CRPC.

Because progesterone is a substrate of CYP17A1, its levels are not decreased by inhibitors of CYP17A1. Instead, they are often increased in patients with CRPC treated with abiraterone.⁵ For progesterone-responsive mutant ARs, a study published in Clinical Cancer Research found that the progesterone-activated T878A-mutant AR was present at high-allele frequency in 3 of 18 patients with CRPC. The study results indicated that tumor cells that express progesterone-activated mutant ARs lead to resistance to drugs like abiraterone that inhibit CYP17A1. The study concluded that suppression of progesterone synthesis could be targeted with AR antagonists and be effective in a subset of abiraterone-resistant tumors.

Novel Agents Under Study

Table. Selected Agents Under Development for CRPC

Nonetheless, abiraterone and enzalutamide remain viable options for patients with CRPC. The randomized phase III ALLIANCE (A031201) trial is currently gathering data from its study of enzalutamide with or without abiraterone and prednisone in patients with metastatic CRPC (NCT01949337). The study will look to OS as the primary endpoint and PSA decline, PFS, objective response rate, toxicity profile, and more as the secondary endpoints. “I think what we can say, pretty safely, is that the combination in this trial of enzalutamide and abiraterone is relatively well tolerated,” Dreicer commented. The trial has accrued quickly, with 1224 patients with progressive CRPC enrolled, and data will mature over the next several years.Several novel agents are currently being tested in the CRPC arena as alternatives to abiraterone and enzalutamide (Table). Relugolix (TAK-385), a highly selective, oral nonpeptide gonadotropin-releasing hormone antagonist, is being investigated in patients with hormone-sensitive metastatic prostate cancer. In a 3-part, randomized, dose-escalation study, patients treated with relugolix demonstrated a good tolerance of the drug, and effective testosterone suppression. Common adverse events included bradycardia, headache, and hot flush (all grade ≤2).⁶“Interestingly, from the FDA’s perspective, if you look at new hormonal therapies, it’s not about activity; it’s about testosterone expression. So, you can get a certain drug approved by certain metrics of [testosterone] suppression and not necessarily whether a certain therapy is better than another,” Dreicer said.

In a phase II trial, patients with metastatic or locally advanced disease who were deemed appropriate for ADT were randomized to 2 different doses of relugolix and leuprorelin. An analysis conducted when 75 patients received more than 24 weeks of therapy concluded that relugolix rapidly reduces testosterone and, similar to leuprorelin, maintains it at low levels (<50 ng/dL and <20 ng/dL) over 24 weeks. The drug had a tolerable safety profile, and PSA responses occurred rapidly during the first 4 weeks of dosing and were sustained throughout the 24 weeks of treatment. After 24 weeks, PSA levels were reduced by 97.3% to a median of 0.1 ng/mL.⁷

Another agent, darolutamide (ODM-201), a nonsteroidal antiandrogen therapy with a limited ability to cross the blood-brain barrier, reduced toxicities related to the central nervous system (CNS). It also does not typically increase serum testosterone. Preclinical evidence suggests that darolutamide blocks the activity of all tested and well-known mutant ARs, according to Dreicer.

In the ongoing phase III randomized ARASENS trial, investigators are assessing the efficacy and safety of darolutamide in combination with standard ADT and docetaxel in patients with metastatic hormone-sensitive prostate cancer (NCT02799602). This trial, which is currently enrolling an estimated 1300 patients, is using OS as its primary endpoint.

Another study, the phase III ARAMIS trial, is assessing darolutamide and ADT in patients with nonmetastatic CRPC compared with placebo and ADT (NCT02200614). The primary endpoint is metastasis-free survival (MFS), with OS as a key secondary endpoint. “The reason these trials are being done, as opposed to looking at more advanced disease, follows what happened with TAK-700, the [CYP17A1 enzyme] inhibitor, which had some potential advantages to abiraterone but fell short,” Dreicer explains. “So, it’s conceivable that, if these trials are successful, there could be a new regulatory pathway for MFS.”

Apalutamide (ARN-509) is another nonsteroidal antiandrogen agent that has preclinical evidence of greater potency and less CNS toxicity compared with enzalutamide. The phase III ATLAS study seeks to assess the efficacy and safety of apalutamide with bicalutamide and ADT versus bicalutamide and ADT alone. Much like in the ARAMIS trial, the ATLAS trial has MFS as its primary endpoint, with OS as a secondary endpoint at 84 months (NCT02531516). This trial will investigate the drug in patients with high-risk localized or locally advanced prostate cancer.

Apalutamide with ADT is also being investigated in the phase III randomized SPARTAN study versus ADT alone. This trial will look at its efficacy in patients with nonmetastatic CRPC who have had no prior treatment with second-generation hormonal agents, radiopharmaceutical agents, chemotherapy, or other investigated agents (NCT01946204). Again, the primary endpoint is MFS and the secondary endpoint is OS.

Seviteronel (VT-464), a nonsteroidal CYP17A1 enzyme inhibitor, is also under investigation for treating patients with CRPC. According to Dreicer, the drug has an approximate 10-fold selectivity for the inhibition of 17-20-lyase over 17alpha-hydroxylase, which results in less interference with corticosteroid production relative to abiraterone. Preclinical data suggest that seviteronel may reduce AR signaling more effectively than abiraterone. A nonrandomized, open-label phase II trial is ongoing, assessing the safety and efficacy of seviteronel in patients with CRPC who were previously treated with enzalutamide or abiraterone (NCT02445976).

According to Dreicer, in vivo and in vitro studies of EPI-506, a speci c small-molecule inhibitor of the AR N-terminal domain, have shown activity against full-length AR and AR splice variants, including AR-V7 . A phase I/II study is investigating the safety and antitumor activity of EPI-506 for patients with metastatic CRPC (NCT02606123).

One of the challenges for new AR-targeted agents, Dreicer noted, is that there will not be a comparative study performed. Further studies are needed to determine the efficacy and optimal sequencing of these agents during the course of treatment.

References

1. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanism of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4(3):365-380. doi: 10.3978/j.issn.2223-4683.2015.05.02.
2. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038. doi: 10.1056/NEJMoa1315815.
3. Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to anti-androgens by bypassing androgen receptor blockade. Cell. 2013;155(6):1309-1322.
4. Chang KH, Li R, Kuri B, et al. A gain of function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013;154(5):1074-1084. doi: 10.1016/j.cell.2013.07.029.
5. Chen EJ, Sowalsky AG, Gao S, et al. Abiraterone treatment in castra- tion-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res. 2015;21(6):1273-1280. doi: 10.1158/1078-0432.CCR-14-1220.
6. MacLean DB, Shi H, Faessel HM, Saad F. Medical castration using the investigational oral GnRH antagonist TAK-385 (relugolix): phase 1 study in healthy males. J Clin Endocrinol Metab. 2015;100(12):4579- 4587. doi: 10.1210/jc.2015-2770.
7. Saad F, Bailen JL, Pieczonka C, et al. Second interim analysis results from a phase 2 trial of TAK-385, an oral GnRH antagonist, in patients with prostate cancer. J Clin Oncol. 2016;34(suppl 2S; abstr 200).