Platinum Sensitive Disease: When to Use PARPi

A discussion on when to optimally use PARP inhibitors in patients with platinum-sensitive recurrent disease and the potential for PARPi re-treatment.

Maurie Markman, MD: Turning back to the PARPs [poly ADP ribose polymerase inhibitors], Mike, what's the optimal time to use a PARP inhibitor in a patient with platinum-sensitive recurrent disease?

Michael Birrer, MD, PhD: Wow, another loaded question. Obviously, based upon ARIEL3, NOVA, and the SOLO trials, we have indications essentially for everybody in that setting. I sort of apply the same equation that I'm now applying for frontline maintenance to recurrent, meaning that if the patients have clear indications of HR [homologous recombination] deficiency, and what I mean by that is BRCA mutations or Fanconi pathway mutations, they tend to get from me PARP earlier than the other patient populations. And whether you work in an HRD assay there or not is up to your preference.

Now, what's muddied the water is that all that's moving upfront, so that brings us to the second question, which is if they've already seen a PARP inhibitor, what do you do? And we clearly don't know the answer to that. There's a small study from Oklahoma that showed a couple of very good responses in patients being re-treated with a PARP inhibitor. But it doesn't answer the question because this is going to be a heterogeneous group of patients. And my prediction would be if you have a reversion mutation where the BRCA gene is put back into frame, those patients won't respond to a PARP inhibitor.

But if you have a progression on a PARP inhibitor from another mechanism like methylation, that could be changeable. So those patients could be re-treated with a PARP. There is a study you should be aware of focused on this. It's called OReO. If you look at this trial design, it will hurt your eyes it is so complicated. But it's going to specifically address, I think, mechanisms of resistance and who would benefit from re-treatment.

Maurie Markman, MD: Wendel, questions?

Wendel Naumann, MD: I think Mike summed that up pretty well. It is a difficult issue. I would say if you look at the duration of PARP therapy in the upfront setting, these trials either had 3 years in PRIMA or 2 years on PAOLA. If they recur and they're not on PARP, it means they're going to be a good ways out from their initial treatment. And I think those are going to be, we look at platinum sensitivity as a marker for homologous repair deficiency. And I think that's an in vivo marker of that process. And so if patients are platinum sensitive, they're probably going to respond to a PARP again if they haven't recurred on the PARP. Now, if they recur on the PARP, I'm not sure that chemotherapy is going to reverse methylation or whatever process that made them resistant to the PARP.

Michael Birrer, MD, PhD: Are you seeing PARP after PARP?

Annette Hood, PharmD, BCACP: We are not seeing PARP after PARP, no.

Michael Birrer, MD, PhD: I'm not sure if we'll be covered from reimbursement either, but it's going to be a big issue in about 2 to 3 years because other than SOLO-1, I don't think we really have any data we're curing anybody. So lots of patients are going to be PARP inhibitor resistant.