Combination PARPi Strategies in Metastatic CRPC: Interpreting Data From Clinical Trials


Key opinion leaders in metastatic castration-resistant prostate cancer management review a subset of clinical trials focused on combination strategies with PARP inhibitors.


Rana McKay, MD:Let’s segue into the series of trials that have looked at a combination ARSI-PARP inhibitor in the frontline mCRPC [metastatic castration-resistant prostate cancer] state. These trials were designed with patients having not necessarily seen modern-day therapy in the mHSPC [metastatic hormone-sensitive prostate cancer] setting. Most patients were not escalated in the mHSPC setting, though that’s the standard of care. We’ve seen controversial data in the all-comers population. There seems to be a benefit with regard to rPFS [radiographic progression-free survival]. There’s a signal for OS [overall survival], but data are still immature. It gets very messy when we start carving out the BRCA1/2-altered patients, the non-BRCA1/2, -HRR patients, and your unknown or negative. It gets very messy. How do you simplify these data for us? I’m looking at you, Sumit. Simplify it for us. The community needs to hear a simple, clear message about how we interpret all these data.

Sumit K. Subudhi, MD, PhD:If we’re going to be truly stringent, we can’t apply these data to our current population of mCRPC because all these patients are getting second-generation hormones in the front line. This is where we go to the old data with monotherapy. That’s where we all feel comfortable giving PARP inhibitors in our BRCA-positive patients. There’s a possibility that you could sensitize. That hypothesis is generating, but we need to prove that. Some of the trials that need to happen are the PARP as a standard of care vs adding the second-generation hormone, as opposed to the other way around, where we’re looking at the second-generation hormone first and then adding on PARP.

Rana McKay, MD:Any thoughts on simplifying these data? As it stands, they’re not indicated in an all-comer population. The FDA label around the PROpel data got released at the end of May, just before ASCO [American Society of Clinical Oncology Annual Meeting]. It approved olaparib approved in patients with BRCA1/2-mutated tumors in the frontline CRPC [castration-resistant prostate cancer] setting when used in combination with abiraterone. That’s quite different from the label for monotherapy. We have a very restricted label. For patients who haven’t been escalated in frontline mCRPC, we can use olaparib-abiraterone for BRCA1/2. Everything else is a big question mark. What do you all think?

Ulka Vaishampayan MD:I agree. There’s some PFS [progression-free survival] benefit, but if we know there’s an overall survival benefit, that may convince us. But it’s in a setting where you’ve never used ARSI before. Do those patients exist in mCRPC. Maybe they still do if you believe the population studies that show that only 40% or so are getting the treatment intensification. In those patients, I may be willing to consider it, but only if there’s an OS benefit.

Rana McKay, MD:In the beginning, when these data were first released, we were all worried about messaging coming out around, saying, “You don’t need to test anybody,” But these data have only reaffirmed the need to test everybody and make sure you’re doing thorough testing. Do you all agree?

Ulka Vaishampayan MD:Absolutely.

Sumit K. Subudhi, MD, PhD:The data also show that we have to go beyond 1 or 2 lines of therapy. [Prostate cancer is] 1 of the few cancers that’s that way. If you look at lung cancer, they look at it histologically. Then they molecularly subsegregate them and allocate different treatments for each of these things. But we’re continuing to treat it as a 1-size-fits-all disease, which it’s not.

Rana McKay, MD:There are now 4 PARP inhibitors: rucaparib, talazoparib with enzalutamide, niraparib with abiraterone, and olaparib with abiraterone. Do you all see PARP inhibitors as all the same? Are they all different, or is it a moot point? The only indication is for olaparib and abiraterone.

Sumit K. Subudhi, MD, PhD:It’s similar to what we’ve seen with the second-generation androgen receptor antagonists. They have different toxicity profiles that can help drive decision-making.

Rana McKay, MD:Any other thoughts?

Scott Tagawa, MD, MS, FACP:They’re more similar than different, but there are slight differences. One of the nice things is that if we’re prescribing a doublet, at least we can figure out if we want the abiraterone or enzalutamide backbone. Then whatever pairs with that.

Transcript edited for clarity.

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