PAOLA-1 Trial Overview

A discussion of the PAOLO-1 trial regimen and the rationale behind combining olaparib and bevacizumab as post-chemotherapy maintenance.

Maurie Markman, MD: Now back to the trials. Mike, the PAOLA-1 trial.

Michael Birrer, MD, PhD: PAOLA-1; so you got the pronunciation right. I’ve heard everything from PAOLA-1 to other things. But it’s an interesting study. It’s not been published yet. I’ll restrict my comments to what was presented at ESMO [the European Society for Medical Oncology annual meeting]. It’s an upfront study that basically took patients, newly diagnosed ovarian cancer patients, who I think was a slightly better population than the PRIMA trial population. And the reason I say that is that they had to be PR [partial response] and CR [complete response] to their platinum-based therapy, and they also could be NED [no evidence of disease], based on their surgery. And in fact, if I recall correctly, 50% of the patients were NED. Then they were randomized to BEV [bevacizumab] as a single agent versus bevacizumab plus olaparib. So this gets at the issue of first of all, how do you deal with the patient population that’s getting bevacizumab, which is what the European population is? And 2) What’s the effect of adding a PARP [poly ADP ribose polymerase] inhibitor, in this case olaparib?

The take-home message in the intent-to-treat patient population, there was a significant hazard ratio in favor of the combination. I personally interpreted it as it’s a safe combination, but I say that with the caveat being that there was an increased discontinuation rate in the combination. And if you then look at how it broke down, there are some interesting data. Remember though, the breakdown is with exploratory end points. These are not definitive end points, but they were prespecified.

If you look at how it breaks down, patients who are BRCA-mutated and HRD [homologous recombination deficiency]-positive benefitted. But if you go into the HR [homologous recombination] proficient group, the PFS [progression-free survival] curves are superimposable, which in itself is a little odd, I think. I would have expected to see then the niraparib effect that we saw in PRIMA added to the bevacizumab. And there should have been a slight difference. The explanation for that is that the comparative arm is an active arm with bevacizumab, and so you don’t quite see it. It’s an important study because I think it will, first of all, probably lead to a very high-level publication, and 2) my guess is it will lead to an extension of the indication for olaparib in frontline beyond germline. In fact, my suspicion is it will get approval for everybody, but we’ll see.

Maurie Markman, MD: Wendel, do you have anything to add to that?

R. Wendel Naumann, MD: No, I think that’s exactly right. I guess the question is, does it change my desire to use bevacizumab up front? I think the decision is how do we choose which patient to go on which regimen. That’s going to be the hardest choice that we have to make.

Michael Birrer, MD, PhD: I only have one comment here I’m sure you’re going to love, Maurie, which is that the studies never really ask the important questions. We always dance around it, particularly when we look at combinations versus single agent. But the real question here is combination versus sequence. If you use these drugs sequentially, do you get the same bang for your buck as if you use them in combination, but you don’t get the toxicity?

Maurie Markman, MD: Is there true synergism in the 2 combinations?

Michael Birrer, MD, PhD: That’s right. No one’s going to do that study, I don’t think.

Maurie Markman, MD: Unfortunately, the more trials we have these days. In the old days, as we all know, it was relatively easy. We do the trial, it was negative, and you go on to something else. Now, when you have positive trials, it just actually asks more questions.

R. Wendel Naumann, MD: I don’t know, you had that same experience with IP [intraperitoneal] therapy.

Maurie Markman, MD: That’s right. There we had a number of positive trials that were ignored, so that’s just the way it goes.