The Biology of Prostate Cancer

Transcript:

Andrew J. Armstrong, MD, MSc: As a medical oncologist, when I see patients in the clinic who have metastatic castrate-resistant prostate cancer, I look at many factors to determine prognosis, not just circulating biomarkers. Many factors include their functional status, whether they have pain, their imaging, and the pattern of spread. For example, patients with liver and lung metastases have a far worse prognosis than those patients where the cancer is confined to lymph nodes or bone metastases. The level of PSA, alkaline phosphatase, and other bone markers—symptomatic disease—a lot of these things factor into treatment decisions. For example, we use certain therapies in men without symptoms, like proline, sipuleucel-T. And we use some therapies based on the FDA label, which include symptomatic disease, such as radium-223. So, many of these phenotypes of prostate cancer, which are basically the manifestations of the disease that you see in the patient, help to determine prognosis and how aggressive we may be as oncologists to treat that patient.

Treatment for these patients is largely dictated by patient preference, the available options, what the prior treatments have been, and the pace of the disease. So, most of these patients have lethal disease, and treatment is indicated. It’s not really a matter of when to treat but what the first treatment will be. There are now many approved options that improve the survival of men with metastatic prostate cancer. And so, it becomes a question of the sequence—using drug A, then B, or B, then A—and which sequence over time will optimize the outcomes for those patients. Some of the other discussion items that we have with patients are the relative risks and benefits, the toxicities of individual treatments, and so that helps inform on the frontline decision.

In the past 5 years, we’ve had really 2 new AR-directed therapies: abiraterone and enzalutamide. Both of these drugs target the ligand-binding domain of the androgen receptor, and they’re very potent. Both drugs improve overall survival. They delay the time that a patient has until they need chemotherapy or until their symptoms deteriorate. It delays progression. Most patients do respond to their therapies. They’re hormonal therapies in nature, meaning their quality of life is generally good. The toxicity profiles are very reasonable, and many patients find these therapies acceptable, and that’s why the choice is really between these 2 drugs as a frontline therapy. Most men have a desire to put off more toxic therapies that may impair their quality of life. And so, these AR-directed therapies are highly effective really for the first 1 to 2 years of that patient’s life.

Abiraterone was initially thought to be an androgen synthesis inhibitor. Many prostate cancers adapt to a low testosterone environment by manufacturing their own androgens. So, they can behave almost like little adrenal glands making their own fuel that fuels their escape from castration. Castration-resistant tumors still depend on the hormone levels and the hormone receptors, particularly the androgen receptor. So, abiraterone reduces these enzymes. It blocks their activity, reduces androgen synthesis.

Since its initial discovery, it has actually been determined that abiraterone is actually metabolized to active metabolites that can block the receptor or even stimulate the receptor. And so, it’s a complex drug, but the main activity is to block the ligand domain action of the androgen receptor.

Enzalutamide, conversely, is really a pure antiandrogen. It blocks the androgen receptor at the ligand-binding domain. It’s a very potent receptor inhibitor compared with first-generation antiandrogens, such as bicalutamide or flutamide, and has superior potency in terms of clinical efficacy but also in terms of some of the safety issues. There’s a little bit more toxicity with both of these drugs than the standard frontline hormonal therapies. Both of these drugs are used in conjunction with androgen deprivation therapy as the frontline standard approach for men with castration-resistant disease.

Transcript Edited for Clarity