PARP Combinations: The Future



Bradley J. Monk, MD, FACS, FACOG: So, you had mentioned combinations. I said, what’s next after SOLO-1, and you said, “Well maybe all-comers,” and Mike told us about the PRIMA study. Tell us about this PAOLA-1 trial, which will be probably the first combination with olaparib [Lynparza] to report. Tell us what that study is about.

Ursula A. Matulonis, MD: That is also in all-comers as well, for patients who are responding to upfront chemotherapy, have advanced disease, and the randomization is around—thinking about bevacizumab [Avastin] as a standard treatment. So, using bevacizumab but then adding olaparib. The rationale would be to try to induce HR [homologous recombination], meaning to try to trick the cancer cell into thinking that it has underlying homologous recombination deficiency [HRD], and therefore making it more sensitive to a PARP inhibitor.

Bradley J. Monk, MD, FACS, FACOG: And that study is anticipated probably in 2019. So, I think the biggest conclusion of SOLO-1 is that placebo maintenance is bad. And we can debate whether bevacizumab is better or worse, but the reality is most patients are not BRCA-mutated, so bevacizumab is still an option on the table. But if you layer them together where all-comers get bevacizumab, and then olaparib on top of that, maybe that’s the next step, and certainly we’ll know very soon as that trial’s completed enrollment. Maybe we should be adding immunotherapy to PARP inhibitors—Dr Birrer, what do you think? Frontline [therapy]?

Michael J. Birrer, MD, PhD: Well, combinations are hot right now and we’ve already talked about the antiangiogenic combination, but the other one is immunotherapy for sure in combination with PARP inhibitors. There’s a theoretic interest in that, right?

Bradley J. Monk, MD, FACS, FACOG: Yes, we talked about that.

Michael J. Birrer, MD, PhD: So, you have a DNA repair abnormality in many of these tumors as we’ve discussed—HRD—that certainly could predispose these tumors to having a lot of neoadjuvant formation, which are antigens, peptides that the body doesn’t normally see, so they should be good targets for T cells. And one could argue that those tumors that are going to respond to a PARP inhibitor would also have a lot of neoadjuvant formations, so they would also respond to immunotherapy, anti—PD-1 [programmed cell death protein 1] as the combination.

Bradley J. Monk, MD, FACS, FACOG: That is such a wonderful idea in many people’s minds, that they’re going to study 5000 patients. And so, if you think of the 6 checkpoint inhibitors that are approved, 4 of them are now entering phase III PARP inhibitor combination trials: nivolumab [Opdivo], avelumab [Bavencio], pembrolizumab [Keytruda], and durvalumab [Imfinzi]. Atezolizumab [Tecentriq], which is the other one—because it’s made by the same company that makes bevacizumab—the atezolizumab combinations predominantly are with bevacizumab. And then Tesaro has [its] own checkpoint inhibitor not yet FDA approved, TSR-022. So, you have nivolumab, avelumab, pembrolizumab, durvalumab, TSR-022—all 5 in randomized phase III trials, with a PARP inhibitor. Do we have 5000 patients on frontline to do it?

Ursula A. Matulonis, MD: Well, I think it is a daunting task too, and I know that, yes, there are multiple phase III trials. And I think it’s just important for centers to really look at them, because the trials are a little bit different in terms of….

Bradley J. Monk, MD, FACS, FACOG: No question.

Ursula A. Matulonis, MD: You know, the addition of bevacizumab—mandatory, not mandatory, when patients can enter on to the trial. Sometimes for academic practice we don’t, and sometimes we do see a lot of patients upfront after surgery, but sometimes patients will be referred in after they start chemotherapy.

Bradley J. Monk, MD, FACS, FACOG: And that’s why the ATHENA trial is a maintenance alone trial, of 1 of the 5.

Ursula A. Matulonis, MD: Exactly, that’s right.

Bradley J. Monk, MD, FACS, FACOG: Just on maintenance.

Ursula A. Matulonis, MD: That’s right, just at maintenance.

Bradley J. Monk, MD, FACS, FACOG: So, I guess when I say, do we have 5000 patients, I would hope that you’d say, “Well look, the NCCN [National Comprehensive Cancer Network] guidelines is the number 1 option clinical trial.” And then I would hope that people would say, “Well wow, with 5000 patients, I ought to be able to find a clinical trial for my patients,” right?

Ursula A. Matulonis, MD: I think, yes, we should be able to do these trials, that’s correct.

Bradley J. Monk, MD, FACS, FACOG: So basically, most cities have one of these frontline, PARP/immunotherapy clinical trials, or atezolizumab/bevacizumab clinical trials.

Michael J. Birrer, MD, PhD: Major academic centers even run 2 or 3.

Transcript Edited for Clarity

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