Future of PARP Inhibitors in mCRPC


Raoul S. Concepcion, MD, FACS: One drug class that’s getting a lot of attention is PARP inhibitors. Evan, give us a little overview about DNA repair genes and those types of things—where, potentially, these could come into play—and the rationale for why this is coming to the forefront.

Evan Y. Yu, MD: We talked a bit earlier about DNA repaired genes. There are many genes, and they’re not all created equal. But, to briefly summarize how they work, they work via homologous recombination. If you have a single strand break, you can oftentimes repair that with something called PARP. The reason we’re leading towards talking about PAPR inhibitors here is that if you already have an acquired germline alteration in a gene—I’m just going to use BRCA2, for an example—you already have 1 hit, there.

Now, in your normal cells, you can repair because you have just 1 abnormal hit, and you have a situation where the other allele is normal. But, in your cancer cell, if you have an abnormal allele there and you have PARP trying to repair things, and you come in with a PARP inhibitor, you end up not being able to repair. That’s called synthetic lethality, and you end up, hopefully, not touching your normal cells but damaging the cancer cells that lead to cell death.

That’s how the PARP inhibitors work. We found, through our Stand Up to Cancer international dream team, that about 20+% of patients have either somatic or germline alterations in this. And 12%—through Pritchard’s New England Journal of Medicine paper—have germline alterations. Groups in the Mateos paper in the New England Journal of Medicine showed that if you give olaparib, a PARP inhibitor, to those patients who are enriched, you get very, very dramatic responses—88%. It’s not 100%, but it is 88%. And also, in patients who aren’t enriched with an abnormality, there still are responses, but it’s very, very small—single-digit numbers. Again, it’s not perfect. It’s not a perfectly predictive biomarker, and you can’t really determine predictiveness without a randomized controlled trial. But, it’s an early start.

Michael A. Carducci, MD, FACP: The current studies are all about looking to see if you can select for that patient population and get responses. How durable are they? And, do they make a difference with the current standards?

Raoul S. Concepcion, MD, FACS: It’s important for our viewing audience to understand that, currently, we’re talking about these PARP inhibitors that are not currently FDA approved for the treatment and management of metastatic castration-resistant prostate cancer. Moving a step forward, we know from a couple of weeks ago that one of the PD-1 inhibitors got approved by the FDA. It is, basically, tumor agnostic as long as you can have a companion diagnostic test. That test is for this mismatch. So, I think this is, hopefully, where people are trying to go. It would be approved regardless of the tumor cell type, but would work off, potentially, some of these biomarkers.

Transcript Edited for Clarity

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