A new generation of agents that target androgen synthesis and AR signaling have provided proof of concept and robust data to support the hypothesis that the androgen pathway remains an important factor throughout the treatment of CRPC.
A new generation of agents that target androgen synthesis and androgen receptor (AR) signaling have provided proof of concept and robust data to support the hypothesis that the androgen pathway remains an important factor throughout the treatment of patients with castration-resistant prostate cancer (CRPC), according to Robert Dreicer, MD, MS.
Although CRPC formerly was considered a “hormone refractory” disease, there are now 2 recently approved antiandrogen therapies and approximately 10 novel agents in development, according to Dreicer in a presentation March 2014 at the7th Annual Interdisciplinary Prostate Cancer Congressin New York City.
Yet there are many unanswered questions about how best to integrate antiandrogen therapies into the treatment paradigm for CRPC, particularly in light of other new agents that the FDA has approved during the past 3 years. “Drug development is outpacing our ability to understand the sequential and combination utility of these therapies,” said Dreicer, who is chair of the department of solid tumor oncology at the Taussig Cancer Institute and a professor of medicine at the Cleveland Clinic Lerner College of Medicine in Ohio.In 2011, the FDA approved the first novel antiandrogen agent, orally available abiraterone acetate (Zytiga), in combination with prednisone for patients with metastatic CRPC based on the COU-AA-301 phase III clinical trial.1The trial showed a survival advantage compared with placebo for patients treated with the abiraterone regimen who had progressed following chemotherapy, providing proof that the androgen pathway remains relevant throughout the course of prostate cancer and that patients need to be maintained at castratelevels of testosterone after progression following primary androgen- deprivation therapy, noted Dreicer. A second phase III trial in the prechemotherapy setting demonstrated that men treated with abiraterone achieved a significant increase in radiographic progression-free survival (rPFS), but the study did not show a statistically significant survival advantage.2Abiraterone works by inhibiting the lyase CYP17, an enzyme important in the pathway of both testicular and extragonadal androgen synthesis.
In 2012, the FDA approved enzalutamide (Xtandi) for the treatment of men with metastatic CRPC who have previously received docetaxel. Enzalutamide, which is supplied in capsules, has a mechanism of action distinct from that of abiraterone; enzalutamide prevents AR interaction and blocks downstream pathway activity. The phase III AFFIRM trial showed that enzalutamide prolonged survival in men with CRPC in the postchemotherapy setting compared with placebo.3In the subsequent PREVAIL trial in patients with CRPC who had not received prechemotherapy, men treated with enzalutamide had an improved rPFS and a 29% reduction in the risk of death compared with participants in the placebo arm.4Novel androgen-targeting agents currently under investigation include lyase inhibitors and AR inhibitors. Because these agents have mechanisms of action similar to those of either of the two agents already in use in clinical practice, it may be difficult to show improvement in efficacy, Dreicer noted.
“The development of these agents has presented us with some interesting dilemmas,” said Dreicer. “The reality is that going head to head in a setting where there are very similar drugs already may not be a strategy for drug approval going forward.”
For example, a second-generation CYP17 inhibitor, orteronel (TAK 700), did not show a survival advantage compared with placebo in an interim analysis of the ELM-PC5 phase III study,5although the drug did show a benefit in rPFS in patients who had previously been treated with chemotherapy. However, a geographic analysis showed that in parts of the world that do not currently have access to either abiraterone or enzalutamide, there was a survival advantage. Other lyase inhibitors in development include CFG920, VT-464, and EN3356.
Likewise, there are new antiandrogens in development. ARN-509, an AR antagonist, is bypassing both the pre- and postchemotherapy settings and is currently being tested in an earlier patient population-patients categorized as high-risk M0, prior to the spread of disease to lymph nodesin an effort to prevent progression to metastatic disease.6Other antiandrogens being explored include ODM-201, AZD-3514, and EZN-4176.
Another agent, galeterone (TOK-001), is considered both a lyase inhibitor and an antiandrogen. Galeterone has 3 distinct mechanisms of actions, according to the NCI Drug Dictionary: (1) as an AR antagonist; (2) as a CYP17 inhibitor; and (3) as an agent that decreases overall AR levels.With the emergence of new active therapies, many clinical questions have emerged. Dreicer told the audience that he uses the “one-third” rule: one-third of patients will be inherently unresponsive to these newer agents, one-third will have short-lived responses of several months, and another third will have long-term responses. The issue for the field is to identify each of these patient subsets, which is currently not possible. As patients are moved from one treatment regimen to another, cross-resistance also may become an issue since the molecular pathways of resistance for these compounds are multiple and may be overlapping.
Other questions not yet addressed in the field are the optimal timing to start these agents and when to stop therapy. “You could argue that maintaining testosterone close to zero is a good thing but the cost of abiraterone may be too high for many patients,” Dreicer acknowledged.
The role of combination therapy in the CRPC setting also remains an open question. One study addressing the potential benefit of combining lyase inhibition with AR inhibition is an Alliance for Clinical Trials in Oncology phase III trial that will randomize patients 1:1 to either enzalutamide or enzalutamide with abiraterone plus prednisone.7
Other issues include whether or not agents that decrease skeletal events are necessary in addition to enzalutamide or abiraterone (because both of these agents alone have been shown to decrease skeletal events in metastatic CRPC patients) and whether or not moving these agents to premetastatic and adjuvant settings can potentially cure patients.
Prostate cancer research will need to address these questions quickly because the increasingly complex treatment paradigm is putting pressure on the development of new drugs, as are the economics of treating patients with the newer, relatively more costly agents, concluded Dreicer.