Treatment Pathways and Sequencing Strategies in CRPC

Publishded Online: Oct 25, 2013

James Mohler, MD

James Mohler, MD

An interview with James Mohler, MD, associate director and senior vice president for Translational Research at Roswell Park Cancer Institute, Buffalo, NY, and chair of the NCCN Guidelines Panel for Prostate Cancer.

Targeted Oncology: How would you characterize the changing therapeutic landscape for castration-resistant prostate cancer (CRPC)?

Dr. Mohler: Hormonal therapy remained mostly unchanged for over six decades after Charles Huggins demonstrated in the 1940s that prostate cancer responded to castration. There were a couple of blips, including the development of chemical castration delivered using LHRH agonist depot injections and the introduction of antiandrogens by Fernand Labrie, both in the 1980s. Over the last three years, five new agents have been approved by the FDA: the hormonal therapies abiraterone and enzalutamide; a new chemotherapy, cabazitaxel; an immunotherapy, sipuleucel-T; and a new form of radiation, radium-223 chloride. With so many new agents, it is easy for men--many of whom have already failed treatment--to become confused about their course of treatment and prospects. We're extending life in clinical trials by 3-5 months on average, and you can get excited about that, especially if the benefits are additive, or remain unexcited that we still need a curative therapy. We know we have to do much better.

Is there a consensus sequencing paradigm?

No. In the early space, some clinicians start hormonal therapy early, but there are increased side effects associated with that. I start hormonal therapy later, and prefer to use it intermittently, a strategy that has demonstrated equivalent survival but improved quality of life and reduced costs. In the castration-resistant space, chemotherapy has been shown to extend survival for about 2 months and is used only in men who are symptomatic because of the side effects. Newer agents extend survival 3-5 months after chemotherapy and they are less toxic than chemotherapy. Abiraterone has some side effects and must be administered with prednisone, while enzalutamide does not, and so some doctors favor it. That is a decision based on convenience. The new thinking is that if we can extend life later in the disease with these new treatments, they should be used earlier, but there are no data on that yet. A pessimist might say, “Do no harm,” as there are side effects associated with the new treatments, but an optimist would say, “Go ahead and use them earlier.”

How is the crop of new drugs changing clinical practice for CRPC?

Many clinicians, including me, are looking at the question of earlier use of agents, as well as how to better sequence them and whether they are effective in combinations. We don't have these answers yet. They are answered most quickly in preclinical trials, but unfortunately in the case of abiraterone, for example, lab mice don't have abiraterone targets; they don't make adrenal androgens, and so this has been a limitation for these drugs. They can be tested in chimpanzees, but there are ongoing controversies over that, and perhaps the only alternative is to study them in humans.

With so many new therapeutic options, what guides decision making in sequencing?