Debate Part 2: mCRPC PARP Inhibitor Sequencing and Toxicity

In Part 2 of this Debate series, Drs. Cathy Marshall, Alan Bryce, and Elena Castro continue their discussion on incorporating mCRPC PARP inhibitor toxicity and outcomes data into practice, as well as how treatment should be sequenced after upfront PARP inhibitor administration.

Dr. Marshall:

There was also a lot of debate about the toxicity of the combination of PARP inhibitor and AR-targeting agents. How are you incorporating these data into your practice today?

Dr. Bryce:

Today, in the US, we don’t have approval for the combinations yet, so I’m not doing combinations off study. That is PARP plus a antigen receptor pathway inhibitor. So in standard of care at this point, I’m just doing monotherapy. But to your point, you’re absolutely right. We’re going to have to think about the toxicities of any of the combinations, and we have to think about the effects of long-term exposure to PARP, because they are myelosuppressive drugs, so it’s something to think about.

One point I would make is we talk about these various combinations, so using different PARP inhibitors, and then using different antigen receptor pathway inhibitors. I’d really emphasize, I would not think about this as a class effect. The PARPs are not interchangeable and the androgen receptor pathway inhibitors are not interchangeable. So I would really evaluate each combination independently of the others.

Dr. Castro:

I entirely agree, and we need to be careful with these toxicities that even when they are at class effect, there’s some differences between the different PARP inhibitors, with neutropenia, for instance, being more frequent with a niraparib, although the combination was given at a lower dose and there were more thrombotic events associated with olaparib. Even when they are the same type of drugs, there may be some differences between them. I guess what will happen in the future is that each of us may get used to a PARP inhibitor in combination, and as Dr. Bryce was saying, we need to respect the combinations that have been investigated. We cannot change the PARP inhibitor with a hormonal agent, but once we get used to one and are confident in the management of the side effects and the toxicities, perhaps this is what is going to happen. Each of us will use one more than the others.

Dr. Marshall:

My last question, we talked a lot that these studies were done in the first-line setting in people who had been treated with ADT alone, which is a population that’s probably declining. What about sequencing after these treatments?

Dr. Castro:

We don’t have evidence that after a patient has already progressed to a hormonal agent from an androgen receptor pathway inhibitor, the addition of a PARP inhibitor will be able to repair that resistance, or whether when we sequence to a different hormonal agent and we have the PARP inhibitor that may increase the efficacy of the second agent. I think we will need to produce that evidence before we actually start doing that. I know this is country dependent and in some countries the sequence of hormones is more frequent, but we don’t have evidence at present for that.

Dr. Bryce:

I agree completely. I think the only evidence we have is that once you use one of the oral androgen pathway inhibitors, the second one’s not going to work very well. And we have ample data to support that at this point. I think to argue that we would then use the PARP hormonal agent combination after progression on one oral agent is really putting a lot of weight into the concept of some kind of synergy in the combination. If you look at the PFS advantage in the unselected population, that synergy signal is not very strong. It’s a very modest benefit.

So in the selected patient, the BRCA population, we have approval for monotherapy. Clearly, as Dr. Castro said, there’s zero data to support going to combination in that setting. But there’s also no need; there’s no need to go to the combination when, in fact, the monotherapy is there. Additionally, we don’t want to ignore the financial toxicity in the US. Why am I going to have my patient pay two copays for two oral drugs in the absence of any demonstrable benefit based on data? So, I would say monotherapy for the patient who gets dual agent therapy for hormone-sensitive disease, then I give them part monotherapy for castration-resistant disease.

Dr. Marshall:

Okay. Thank you so much. It was great getting your opinion on this slightly controversial topic, and I’m sure there’ll be more to come, as you mentioned, with FDA decisions going forward. Then, we’re really looking for more data too from these trials reading out with overall survival data as well. So, thank you again.

View their previous comments in Part 1 of this Debate series: mCRPC PARP Inhibitor Monotherapy, Combined With AR-targeting Agents, and More.