Sequencing Puzzles in CRPC Therapies Remain Unsolved

Published: Thursday, Jan 23, 2014
Dr. James L. Mohler

James L. Mohler, MD


Associate Director
Senior Vice President
Translational Research
Roswell Park Cancer Institute
Buffalo, NY

So many new agents for the treatment of men with castration-resistant prostate cancer (CRPC) have been introduced in the past several years that optimal sequencing of therapies remains an unsettled question, according to James L. Mohler, MD, chair of the National Comprehensive Cancer Network’s Guidelines Panel for Prostate Cancer. Mohler, a translational research leader at Roswell Park Cancer Institute, addressed sequencing issues in a recent interview with OncologyLive.

OncologyLive: How would you characterize the changing therapeutic landscape for CRPC?

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.

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 because 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 castrationresistant 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 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.

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?

The only definitive information available about the new agents comes from trials in which they’ve been used singly after chemotherapy failure. To date, most decisions are made on the basis of side effects and not on relative efficacy. There is no information comparing one to another, nor about combinations, which can be beneficial or detrimental. We don’t know yet. Under the old medication regimes, combining Lupron with antiandrogens had a small benefit, but then combining orchiectomy with antiandrogens showed no benefit. We don’t want to repeat the mistakes of the past and spend millions on untested sequences and combinations that don’t end up adding anything.

The earlier antiandrogen receptors don’t compete with dihydrotestosterone (DHT) for the androgen receptor ligand-binding domain, the pocket in which DHT binds to activate the androgen receptor. The new antiandrogens are better but still compete poorly with DHT at the ligand-binding domain, and there is still room for improvement. My hope is for better antiandrogens, and there are some small-molecule drugs in development as well as some antiandrogen receptor drugs that act at areas different from the available antiandrogens. The problem is that it takes a long time to test whether the benefits exceed the side effects, and then we also have to think about expense.

What do we know about the efficacy and safety of the new drugs?

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