Robert Dreicer, MD, MS
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 two recently approved antiandrogen therapies and approximately 10 novel agents in development, Dreicer said during a presentation Saturday at the 7th Annual Interdisciplinary Prostate Cancer Congress
in 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 three 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.Currently Approved Agents
In 2011, the FDA approved the first novel antiandrogen agent, orally available abiraterone acetate (Zytiga), in combination with prednisone for patients with metastatic CRPC patients based on the COU-AA-301 phase III clinical trial.1
The 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 castrate-levels 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 (rPSF) but the study did not show a statistically significant survival advantage.2
Abiraterone 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.3
In 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.4More Agents in Pipeline
Novel 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 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, although the drug did show a benefit in rPFS in patients who had previously been treated with chemotherapy.5
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 post-chemotherapy 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 nodes-in an effort to prevent progression to metastatic disease.6
Other 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 three 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.Clinical Questions Abound