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Precision Medicine Has Emerging Role in mCRPC

Angelica Welch
Published: Friday, Oct 06, 2017

One of those biomarkers is called mismatch-repair deficiency, or microsatellite instability. This is another DNA-repair deficiency, but is different from the first one that I mentioned. This one creates many more mutations that makes a cancer more foreign-looking to the immune system, and much more susceptible to an immune checkpoint inhibitor. In fact, pembrolizumab (Keytruda) was approved this year for all cancers, regardless of tissue of origin, who have these types of mismatch-repair deficiencies, including prostate cancer. 

Finally, I touched on other emerging biomarkers and some of the biomarkers that are selecting for novel experimental agents as a way of looking forward.

Currently, how do you decide who receives sipuleucel-T? 

Sipuleucel-T has been around for many years now; it is an FDA-approved, effective agent known to improve survival. Some of the most important data sets about who benefits more from this therapy than others have come from an analysis of a phase III study. This looked at what is called the prostate-specific antigen (PSA)-quartile data of patients with a low-disease burden, such as low PSA.

At Duke Cancer Institute, our median PSA for choosing sipuleucel-T is about 7 but, in this phase III trial, it was about 20. In patients with mCRPC who have a low PSA who are minimally symptomatic had a survival benefit of about 13 months, as opposed to about 2 months for those men who were selected for this therapy and their PSA was over 100, suggesting that early use of immune therapy may result in a greater survival benefit. 

The second major data set was presented, but not yet published, at the 2017 AUA Annual Meeting. We presented data on sipuleucel-T in African Americans, which showed that when matched for disease burden, African Americans have a much greater survival benefit with sipuleucel-T than their Caucasian counterparts.

There are theories about why this may be. There are biological explanations for why inflammation may be increased in these patients, and why that may predispose them to a greater response to a tumor vaccine. But, this is borne out. With lower PSA quartiles, African-American men had a superior outcome quartile by quartile. This is unusual in this situation, where we know that African-American men typically have more aggressive prostate cancer and worse outcomes with almost every other study. This is good news. 

This has changed our practice. We certainly want to make sure we offer sipuleucel-T to patients early in their disease course, and particularly for African-American patients.

Could you share your insight on the Epic AR-V7 assay?  

The Epic AR-V7 assay is a commercial assay. We are externally validating this in the large PROPHECY study. PROPHECY…is testing multiple predictive biomarkers in men with mCRPC taking standard-of-care therapy with abiraterone or enzalutamide. We draw blood before, during, and after these therapies to see if the circulating tumor cell biomarkers can predict whether they will benefit. This is to follow up on important papers published in the New England Journal of Medicine and JAMA, which showed that these are predictive biomarkers in small institutional studies.

What related ongoing trials are in this space?

There are multiple phase III trials and different PARP inhibitors made by different companies—AstraZeneca has the PROfound study of olaparib versus physician’s choice of abiraterone or enzalutamide. These are only in biomarker-selected patients. Rucaparib (Rubraca) and niraparib (Zejula) are also active PARP inhibitors. They are approved in [ovarian cancer], but are not yet approved in prostate cancer. These phase III studies, particularly with a biomarker-selected patient population, are attempting to prove that PARP inhibitors are better than best available standard of care.

What about immune checkpoint inhibitors?

Immune checkpoint inhibitors are all over the place in prostate cancer. They are being looked at in combination with enzalutamide, in combination with PARP inhibitors, radium-223, and docetaxel. They are also being looked at by themselves. There are multiple companies with PARP inhibitors looking at these options. 

At Duke Cancer Institute, we are looking at multiple combinations, including early disease combinations with radiation. The field is wide open right now.

Is any class of drugs more logical, in your opinion?

The idea is that, by themselves, these drugs are not active. We know from kidney cancer and bladder cancer that these drugs need a little bit of a kick start from other therapies. When you biopsy prostate cancer, there is often an immune desert—there are not a lot of immune cells there. Something must happen to get the immune cells there—radium-223, radiation, or double immune checkpoint blockade—something to elicit an immune response and then the checkpoint inhibitor can take advantage of that.


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Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
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