An Overview of PARP Inhibition in Metastatic CRPC

Video

Focusing on the advent of PARP inhibitors in metastatic castration-resistant prostate cancer, genitourinary cancer specialists provide an overview of clinical trials and agents in this setting.

Transcript:

Evan Y. Yu, MD: Let's come back to this topic of DNA repair and PARP inhibition. There's a lot of data in this field now, and Pedro, I'm going to ask you to walk us through the data that exists and some of the exciting things you think that are going on in this area.

Pedro C. Barata, MD, MSc: With PARP inhibition, right?

Evan Y. Yu, MD: Yes.

Pedro C. Barata, MD, MSc: We can present it in many ways. We learned a lot from our friends in breast cancer, ovarian cancer world. Understanding that when we have a deficient gene, which we tend to talk more about that, initially we talked more about the DNA repair, a group of genes. When you have a problem in that family of genes, you can exploit that. You can exploit it in your favor. You do that by inhibiting the PARP which helps to repair DNA and therefore you can control cancer growth and proliferation. With that said, we have a number of PARP inhibitors that have been explored in many solid tumors, or proved in many solid tumors, and the same is true in prostate cancer. We do test for it. We do expect around 10, 12% germline we're born with those. It depends on the setting, but in the CRPC if I quote around 20% I won't be too far. If you add those both, you expect 20 to 30% of those alterations, both germline combined with somatic. That's the biomarker. And that opened the door to target approach with PARP inhibition. I separate the studies that we have into 2 groups. One is a biomarker-based approach and that's where data from the start with de Bono group and then of course PROfound phase 3 trial that's CRPC randomizing to physician choice which was NHT. And of course, we separated by the biomarker but very common BRCA 1, 2 ATMs and then the other group and we improve outcomes in terms of our PFS [progression free survival] which was acceptable by the overall survival and also quality of life is also better. In other words, patients do way better in the context of biomarker disease and this is pre-chemotherapy. And then especially in the cohort A at the time, which was the BRCA ATM story. And then we also had data phase 2 with rucaparib with the TRITAN study, post docetaxel in one monotherapy in docetaxel and is a phase 2, everybody got rucaparib and it was a proof-of-concept study, got preliminary approval and we're waiting for data from the phase 3. And basically, it kind of shows that patients benefit from that drug, rucaparib. We learned from it, when we put all these data together again, biomarker-based approach, is when we look at rucaparib for instance you had 3 cohorts. And remember, the CDK 12 was stopped early for fertility. And even the ATM was not clear whether there was something there. That data together taught us that we started from if we have a biomarker, we making progress to the point where it doesn't matter what biomarker you have and it seems today is relatively consensual that BRCA 2 seems to be the strongest marker driving the signal and then the others kind of seemed to follow. And we can debate about what happens to the less common ones like BRAF 51, etc.

Evan Y. Yu, MD: I'll be too.

Pedro C. Barata, MD, MSc: That's one part of the story. And then we had the other group of studies that explore PARP inhibition in combination with potent NHTs in the absence or not necessarily in the presence of biomarker.

Evan Y. Yu, MD: This is new data from GU ASCO [American Society of Clinical Oncology Genitourinary]?

Pedro C. Barata, MD, MSc: It's very new data from ASCO GU and we got some update at ASCO, but I'm thinking about PROPEL and MAGNITUDE. Let me address first the magnitude because it explores a new drug I haven't mentioned, niraparib and in addition to that because it is 2 separate things. Biomarker negative, biomarker positive. Biomarker negative was stopped for fertility and basically that made sense based on what we learned so far. But then we look in the biomarker positive the combination of an NHD with niraparib or combination was promising. We're waiting to see overall survival, some markers are not ready for prime time. Nonetheless, there's a signal there, especially if we think of the BRCA. Going to back to PROPEL, that's the one that was kind of unexpected to some of us because just a reminder for the design, again, everybody got, well, everybody got ababirateronei plus minus olaparib or a placebo and in the first line CRPC setting but you did not require the presence of a biomarker. And what happened was, you got those patients based on tissue and or circulating tumor DNA and the results, in my opinion, are very striking because the benefit in terms of our PFS seems to be very good, clinically significant in my opinion but is interesting is if you look at the biomarker negative or an absence of a biomarker, we cannot say it's a negative study there. The problem that I see with that data in particular is because it's one piece of data part of the phase 3 trial and where all the other studies are suggesting something different. We need to validate that in further investigation for the studies because we need to settle the question. Do we need the biomarker for us to consider a target therapy of PARP inhibitor or you don't need that if you combine it with NHT in this situation in this case abiraterone was the drug tested? And before I stop and I'm curious to see what my colleagues have to, what their thoughts are about that, I'm just want to say there are other PARP inhibitors out there being investigated and also in different settings. Not only CRPC but also hormone sensitive. I must highlight toluzeparide data, the LEVERAGE phase 3 trial, TALAPRO-3. And there's a number of PARP inhibitors that are not exactly the same the way they act, but nonetheless we are, right now we have olaparib and rucaparib approved. Olaparib regardless of the biomarker, even though we have a post-marketing study going on to identify for the rarer genomic alterations whether the signal is still there or not. And rucaparib we're waiting for phase 3 to confirm those results in the post-docetaxel setting. Going back to our patient, he could have gotten olaparib for instance if he had one of these genomic alterations. And then we have other PARP inhibitors that are going to follow, and we are seeing promising data with activity as we would expect in the context of biomarker positive. It remains to be answered is what are we going to do with patients that do not harbor those alterations? Is that a role for those agents?

Evan Y. Yu, MD: That was a beautiful summary, Pedro. Thank you so much.

Transcript edited for clarity.

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