Sequencing Puzzles in CRPC Therapies Remain Unsolved

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?

There is a smorgasbord of new treatments, and the hope is that each agent associated with extension of survival is additive, but we don’t know that yet. We hope to turn prostate cancer into a chronic disease, but we’re not there yet.

Abiraterone requires coadministration with prednisone and is fairly well tolerated. It extends survival about 4 months on average.

Cabazitaxel is sometimes used when docetaxel fails, although treatment with docetaxel can be repeated, and some patients respond to that. The main toxicity with cabazitaxel is bone marrow suppression and other side effects associated with chemotherapy. It extends survival for about 3 months on average.

Sipuleucel-T is well tolerated, but its efficacy is hindered by our inability to assess response; it doesn’t affect prostate-specific antigen (PSA) but it does extend survival. It appears to stabilize the disease, and the field has been so surprised that it works that the science behind the why has lagged behind its use. The fact that immunotherapy works in CRPC surprises me, as there is a large disease burden at this stage of the cancer, and it therefore should have a poor immunological response. It should be tested in patients with relatively small burdens of disease, but no one can afford to test in the early space because these patients are going to live so long, as many as 20 years and more.

Radium-223 chloride, a new approach to radiation, carries radiation to areas where bone is being repaired through new cell growth near metastases, and its short-range tissue penetration allows it to kill the metastatic prostate cancer and not the surrounding tissue, including bone marrow. The safety profile is better than standard radiation, but you can’t give it simultaneously with chemotherapy. This is a nuclear medicine-based treatment that is helpful at the end of life when the disease is painful.

What are we still learning about sequencing in CRPC?

The major unanswered questions from a therapeutic standpoint are whether these agents will work better if they’re given earlier in the course of disease—or if they’re given together, whether they will achieve synergies or make the situation worse. We have no idea. The third is a societal question. We can add a half-million dollars to the treatment of every man, but should we? This is a moral and ethical question that is not being addressed largely because of its difficulty. It is easy to understand why doctors do not want to deny treatment to any individual, because many men do have a 1- to 2-year response to treatment, but it would be much more cost-effective if we could learn which patients are the good responders and which are not. But these studies have been difficult to fund. We need biorepositories of tissue and greater investment in longer but more important clinical trials. The amount of resources we dedicate to these studies remains too low.