Novel Maintenance Combination in Advanced Ovarian Cancer - Episode 3

Implications of PAOLA-1 in Advanced Ovarian Cancer

November 21, 2019

Bradley J. Monk, MD, FACOG, FACS:PAOLA-1 was a randomized phase III trial of 537 patients. It was presented at ESMO [the European Society for Medical Oncology Congress] 2019, in Barcelona, Spain, during the Presidential Symposium. It was a randomized phase III trial taking the current FDA approval of bevacizumab with chemotherapy, and in maintenance, and adding in all comers with olaparib in the maintenance phase.

So we have chemotherapy-bevacizumab and bevacizumab maintenance versus chemotherapy-bevacizumab and bevacizumab-olaparib maintenance. The primary endpoint of this trial was intention-to-treat. It met its primary end point, with a hazard ratio of 0.59. That’s a good number, and that’s impactful because it was better than bevacizumab. There are other frontline trials, but they’re all versus placebo. It’s much tougher to beat an active control, and it did.

In fact, in the all-comers population, it increased progression-free survival by about 6 months. But more important, in the molecular signature-positive groups, such as the HRD [homologous recombination deficiency] group, there was a 14-month improvement. This is very, very interesting. The hazard ratio for HRD-positive was 0.43. These are unprecedented numbers outsideBRCA. But even in theBRCAgroup, it was a hazard ratio of 0.3. This really is changing the standard. I get it that we got bevacizumab approved in June 2018. I get it that many of us use bevacizumab. But now, if you have aBRCAmutation or an HRD, which is aBRCA-like mutation, I think most of us are going to begin adding olaparib to the bevacizumab, assuming it gets FDA approval. I think that’s almost a certainty.

That has to be weighed against the toxicity—both financially and patient related. And really, the only way we can justify this is if we’re curing more patients. And I think there’s a real possibility. Because if you look at the medians of the combination of olaparib and bevacizumab, they’re unprecedented. In some of those analyses, we haven’t even reached the median after many years. So we’re excited about the possibility of cure. Only time will tell if there’s an overall survival advantage.

I get it that the combination is more toxic than the individual agents. There was no signal that olaparib made bevacizumab more toxic or that bevacizumab made olaparib more toxic. That’s not the point. It’s just that more agents have more adverse events. But there were no new safety signals identified. Bevacizumab, as you know, was associated with hypertension, proteinuria, and so on, as the most common adverse events. Olaparib was associated with fatigue, gastrointestinal disturbances, and bone marrow suppression. There was no exacerbation of the toxicities of either agent alone.

Again, the standard is changing—from June 2018 to bevacizumab alone to now adding olaparib in the maintenance phase, particularly in the patients who have a homologous recombination repair deficiency and those who have aBRCAmutation.

Transcript edited for clarity.