Debate Part 1: mCRPC PARP Inhibitor Monotherapy, Combined With AR-targeting Agents, and More

In Part 1 of this Debate series, Drs. Cathy Marshall, Alan Bryce, and Elena Castro discuss whether PARP inhibitors should be used as monotherapy or in combination with AR-targeting agents for mCRPC, as well as in patients with HRR-mutated disease.

Dr. Marshall:

Hi everyone. I’m Dr. Cathy Marshall, Assistant Professor of Oncology at Johns Hopkins. Today we have very special guests with us today to talk about PARP inhibitor use in prostate cancer. First, we have Dr. Elena Castro, Consultant Medical Oncologist in GU Oncology at the University Hospital, 12th of October, in Madrid, Spain, where she leads translational research in prostate cancer. We also have Dr. Alan Bryce, Medical Oncologist at the Mayo Clinic in Arizona, where he’s Professor of Medicine and Chair of the Mayo Clinic Genitourinary Disease Group.

Right now, we have FDA approvals for PARP inhibitors as single agents in second-line and beyond for men with metastatic castration-resistant prostate cancer, but only for selected populations of patients based on the presence of mutations in some of the homologous recombination pathway genes. But more recent data has emerged that’s really shaking up when we use these drugs and in whom we use these drugs. My first question: should PARP inhibitors be used as monotherapy or in combination with AR targeting agents? Dr. Castro, would you like to start?

Dr. Castro:

Well, I think that for patients with BRCA alterations, for instance, we should use PARP inhibitors as soon as possible. So ED approvals are to be used in combination with androgen receptor signaling inhibitors. Perfectly fine using those in combination for these patients. And actually, Alan did a fantastic job at ASCO GU, presented the data from the TRITON-3 trial that clearly demonstrates the benefit for these patients compared to any other available therapies for advanced prostate cancer. I guess the debate and the controversy is now in the combination for patients without these BRCA alterations.

Dr. Bryce:

Thank you, Dr. Castro. It was a pleasure. We shared the stage for that session and a lot of great discussion. So, the conversation continues. In the US, at the moment, our approvals are for monotherapy in selected patients with qualifying germline or somatic alterations, but we know that the judgment from the FDA is forthcoming with regards to combination therapy. In the combination setting, clearly for the BRCA mutant patients, especially BRCA2, we could see very significant benefit. It’s the question around the other alterations, the unselected patients, where the controversy remains and deep dive into the data is so very important. But I absolutely agree with Dr. Castro’s comment; we probably want to get PARP inhibitors as early as we can for patients with BRCA alterations. And then, you start to think about the other alterations. What should we do? There’s probably some nuance there, but for BRCA, I would try to access a PARP inhibitor as soon as a patient can get one.

Dr. Marshall:

That’s a great segway into my next question: are we going to be using PARP inhibitors for everybody without any biomarker or diagnostic testing to see if they have one of these either germline or somatic mutations? An then, the second part of that is how are we even defining HR mutations? It seems like many of the studies use different definitions.

Dr. Castro:

So, in the different trials that I have investigated, both PROpel and TALAPRO-2, I have seen a benefit in RPFS for patients without the biomarker, without the HRR alterations. Perhaps there is an issue with the biomarker. We may be missing some alterations. We may be misclassifying some patients. The truth is that we have to stick to what we know at present, and there is basically the presence of genomic alterations. But there may be some other transcriptomic alterations or other genes that are not defined as HRR genes that may also sensitize to PARP inhibitors. I agree we have a bit of an issue with the biomarker itself.

Dr. Bryce:

I feel the same way. I continue to believe that PARP inhibitors are targeted therapies, so they work in certain patients, but we shouldn’t overlook the fact that when we look at breast cancer and ovarian cancer, the definition of what qualifies as HRR deficient tumors is different tumor-by-tumor. The qualifying aberrations for PARP inhibitors in breast and ovarian cancer are different than prostate. That probably shouldn’t be the case. When we think about targeted therapies, obviously efficacy varies by tumor type, but the essential mechanism should remain the same. So, I believe that there is a larger list of whether genomic or proteomic alterations, abnormalities in cells that can qualify patients to benefit from PARP inhibitors. We just haven’t figured out that full list yet.

View their continued comments in Part 2 of this Debate series: mCRPC PARP Inhibitor Sequencing and Toxicity.