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Challenges in mCRPC Landscape Surround Sequencing, Biomarkers, and PARP Inhibition

Chelsea LoCascio
Published: Wednesday, Nov 22, 2017

Tanya Dorff, MD
Tanya Dorff, MD
While progress has been made in the management of metastatic castration-resistant prostate cancer (mCRPC) with the addition of targeted therapies to the armamentarium, there are still several unresolved issues, according to Tanya B. Dorff, MD.

on Genitourinary Cancers, Dorff, an associate professor of clinical medicine at University of Southern California, discussed several important components regarding mCRPC treatment, including the addition of novel drugs, optimal therapeutic sequences, and the identification of predictive biomarkers.

OncLive: What agents do you currently look at when a patient’s disease progresses?

Dorff: The questions are how to best use the tools we have, which include abiraterone acetate (Zytiga), enzalutamide (Xtandi), docetaxel, cabazitaxel (Jevtana), radium-223 dichloride (Xofigo), and sipuleucel-T (Provenge). It has obviously gotten a bit more complicated as Dr Guru P. Sonpavde said in his talk [during the meeting] about upfront intensification…We would approach the patients with single sequential therapy, and, typically, we might want to use immunotherapy earlier rather than later.

Some of the newer agents, including immunotherapy, such as pembrolizumab (Keytruda), or PARP inhibitors are in clinical trials. They are in clinical trials that are early, so they are often combined with abiraterone acetate, enzalutamide, or one of our existing drugs—or they're being compared against one of the existing agents. If patients are going to access some of the more novel therapies beyond what we already have, they need to be referred earlier for clinical trials.

Are there biomarkers that are currently being explored for this population?

There are 2 major biomarkers that I discussed during the meeting. One is the PARP inhibitor story with the DNA-repair deficiency. There is increasing recognition that this is common. We should probably be testing for germline mutations in our patients with metastatic prostate cancer, since between 10% to 20% of them will harbor germline DNA-repair deficiency. Obviously, that’s a lot of patients to be testing, so some of us are selecting patients on the basis of family history.

Then, there are somatic mutations in those pathways, as well. Those seem to be strong biomarkers that predict for potential benefit from PARP inhibition. Although, in an interesting plot twist, it looks like they will predict for response to androgen receptor (AR)-targeted therapy, as well. Whether it is just prognostic or whether it is the crosstalk between AR and PARP is an evolving story, but it’s becoming increasingly clear that we need to be screening patients for things like BRCA and other DNA-repair deficiencies.

The other major biomarker, of course, is AR-V7, which has been a really interesting rollercoaster story. It looked initially like AR-V7 was really “it.” It could predict whether someone was going to benefit from abiraterone acetate or enzalutamide, or whether we ought to go to chemotherapy. Then, these studies started coming out that showed that patients with AR-V7 expression were responding to enzalutamide.

I highlighted a clinical laboratory improvement amendment-certified assay in California. There are probably other places you can get the test, and we might use it if you want to choose what's next for the patient. Maybe you would use chemotherapy next, but I wouldn’t use it to say, “This patient should not ever get enzalutamide or abiraterone acetate,” because then we are potentially denying those patients what could be effective therapy.

What factors do you look at to consider the optimal sequence of therapies?

It's a tough question. There are often 2 good choices for an individual patient, but there are some patients for whom I might prefer abiraterone acetate that might be an elderly patient who is frail, maybe has had some falls, neurologic issues, or has had weight loss, because those are all side effects that we can see more with enzalutamide. I might start with abiraterone acetate for them.

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