Robert Coleman, MD, Texas Oncology, The US Oncology Network, Woodlands, TX, discusses findings from a post hoc exploratory analysis of the ARIEL3 trial, which further evaluated the efficacy and safety of rucaparib maintenance in patients with platinum-sensitive, recurrent ovarian carcinoma who are homologous recombination deficiency (HRD) negative.

The findings from this analysis were presented at the 2022 ASCO Annual Meeting.

Transcript:

I'm Rob Coleman, I'm a gynecologic oncologist in Houston, Texas, and I serve as the chief scientific officer for US Oncology Research. I'm also a gynecologist oncologist in Texas Oncology in The Woodlands, Texas.

The poster I'd like to present for you today was involving another trial that we had done with the drug rucaparib, which is a PARP inhibitor, that we had previously reported. I was fortunate to serve as the PI for that trial, where we evaluated the efficacy of rucaparib in women who had platinum-sensitive recurrent ovarian cancer. And they were randomized to rucaparib vs placebo.

And in this particular trial, many of you may remember, we had an analytical pathway that looked at first patients with BRCA-mutated tumors. Secondly, we classified a group of homologous recombination deficient tumors, which included the BRCA population. And then the third was the intent-to-treat population. And the study was positive for all three end points, and of course, received an FDA label for the treatment of patients with platinum-sensitive recurrent disease.

Now, part of that analytical story was to evaluate the subgroups because lots of people ask, "Well, what if I know some of the things you just said? What if I know that the patient does not have a BRCA mutation? Or what if I know that the patient's tumor does not have homologous recombination deficiency? How does the drug perform in those particular settings?" Well, we have some idea of what that was when we did the subgroup analysis in the primary evaluation, but in the poster that we presented here today at ASCO, we looked at the population of patients that we think would have the least likelihood to benefit from PARP inhibitor. And that was the patients whose tumors did not have a BRCA mutation or did not have homologous recombination deficiency signature as identified by the Foundation Medicine test with a loss of heterozygosity score of 16% or more.

We didn't expect to see much of an effect there, but as we showed in the poster, that this isolated subgroup did appear to have a benefit with the treatment of rucaparib. Now, I always want to make sure that we don't overstate what I just said. This is a hypothesis-generating exercise, which means that if we want to prove this, we actually need to do a study where that is the eligibility criteria. But it does raise the hypothesis, and I would say maybe raises some question as to why? Why do we see in a treatment effect, in a patient population whose tumors did not have a vulnerability where we would expect PARP to work?

And there's lots of different ways you could look at this. In my opinion, it's probably that our testing algorithm is probably not specific enough to actually identify the real world deficiency in these tumors. That's something that's going to take longer to sort out. The other is that there may be other mechanisms by which PARP inhibitors work that were not classified under our common understanding of homologous recombination proficiency.

So lots of good questions that were addressed from this particular cohort analysis, but we showed that the effect was robust across all of the subgroups that we had evaluated. And so I think it provides important fodder for future discovery, because if you think about it, as we get better at identifying the patients who benefit, it also raises questions about how we can maybe either overcome resistance that emerges or how we could affect better efficacy in patients that we would not expect benefit. I think, though, that's the exciting part of this and I think this particular poster helps to drive that narrative forward for our next investigative efforts.

Source:

Coleman RL, Oza AM, Lorusso D, et al. Efficacy and safety of rucaparib maintenance treatment in patients from ARIEL3 with platinum-sensitive, recurrent ovarian carcinoma not associated with homologous recombination deficiency. Presented at: ASCO Annual Meeting; June 3-7, 2022. Chicago, IL, and virtual. Abstract 5544.