The PAOLA Trial: Layering PARPi Onto Antiangiogenic Therapy

Bradley J. Monk, MD, FACOG, FACS:That’s the point. We like bevacizumab, at least in some patients.

Thomas J. Herzog, MD:The hazard ratio is 0.72. Then you come in with these hazard ratios of 0.48, for example, and really very close to that, where do you get the biggest bang? Now obviously you’re buying more months with that 28% improvement upfront, but that’s the question.

Bradley J. Monk, MD, FACOG, FACS:But that’s the point, let’s use both. Let’s use PARP [poly ADP ribose polymerase] inhibitors and bevacizumab.

Thomas J. Herzog, MD:Well, in bevacizumab after bevacizumab, we do have data.

Bradley J. Monk, MD, FACOG, FACS:We can do that. At least in the United States, we can always use bevacizumab again.

Thomas J. Herzog, MD:Yes.

Bradley J. Monk, MD, FACOG, FACS:That’s the third trial at ESMO [the European Society for Medical Oncology].

Thomas J. Herzog, MD:Right.

Bradley J. Monk, MD, FACOG, FACS:It was a European trial because when it was done, we didn’t have bevacizumab approved in this country, but still it’s a global approach. Bevacizumab versus olaparib layered in all comers in the maintenance phase. What do you think of that result?

Thomas J. Herzog, MD:Well, PAOLA-1 is the trial you’re talking about, and again, they are very impressive data. They allowed neoadjuvant therapy and so forth. They also had a 2-to-1 randomization similar to PRIMA. They gave the maintenance bevacizumab for 15 months, and then it was randomized to either olaparib or placebo for 24 months. That was the design in that trial. A large trial again: 762 patients enrolled in the 2 arms.

And again, I think it provides a great option for those patients who start on bevacizumab, right? They’re having a benefit, and you don’t know if you want to take that benefit away. And so this provides the option then, at maintenance, to add a PARP inhibitor. Now, there are some things you need to think about with this trial, and 1 is toxicity. Cost, we can discuss if we have time, but there was real toxicity to the patient: dose reductions, dose interruptions and discontinuations were higher.

Bradley J. Monk, MD, FACOG, FACS:Discontinuations for bevacizumab were 6% versus 20%.

Thomas J. Herzog, MD:That’s right.

Bradley J. Monk, MD, FACOG, FACS:And you can see that we’re getting better at administering bevacizumab. When we did our phase III GOG-218 trial, it was 21%. Now it’s 6%. We’re better at managing hypertension, we’re better at keeping patients on treatment, and if you keep patients on treatment, they have a higher potential to benefit. But with the combination you’re right, it’s more toxic, and we haven’t talked a lot about toxicity. There’s a small, maybe 1% to 1.5%, chance of leukemia. We’ve got the GI [gastrointestinal] toxicities, the fatigue, and the bone marrow toxicity. I still like it though.

Thomas J. Herzog, MD:Well, I like it because it gives you that option for my 40%, 50% of patients I have on bevacizumab. In your case it’s going to be higher than that perhaps. And then you feel confident that it hit the mark, right? But the only thing is the bevacizumab-only arm. All these trials are missing 1 arm, especially VELIA and PAOLA-1, in my opinion. The contribution effect there of trying to separate out bevacizumab versus olaparib in that arm, but the hazard ratio is 0.31 for those who had a mutation, and then I think overall it was 0.59.

Bradley J. Monk, MD, FACOG, FACS:Let’s talk about 0.31. People say, “Well that’s as good, that’s as good as SOLO-1.” So why don’t I just use olaparib alone? Let me tell you. You teach me all this stuff. If you can’t beat something, compete against nothing.

Thomas J. Herzog, MD:Yes. Active comparators, yes.

Bradley J. Monk, MD, FACOG, FACS:Well, this is the only trial that actually tried to compete against something, and it still won.

Thomas J. Herzog, MD:Yes.

Bradley J. Monk, MD, FACOG, FACS:So, the confidence here in the therapeutic benefit is even higher. Even though the hazard ratio is virtually identical to olaparib alone, olaparib was versus placebo. PAOLA-1 is versus bevacizumab. And there are a lot of patients in the olaparib-alone arm with aBRCA-mutated disease course who are not cured. So you can improve on that with the combination. I used to stop the bevacizumab when it was aBRCA-mutated patient and pivot to olaparib. Now I want to give both.

Thomas J. Herzog, MD:Yes, I understand.

Bradley J. Monk, MD, FACOG, FACS:And why? Because I’m hoping that I can cure more patients.

Thomas J. Herzog, MD:Right. I understand, I completely understand the rationale. Not allowed to look at the medians because for so many reasons you just looked at them….

Bradley J. Monk, MD, FACOG, FACS:But they’re huge.

Thomas J. Herzog, MD:But by far of the 3 trials….

Bradley J. Monk, MD, FACOG, FACS:They’re the biggest.

Thomas J. Herzog, MD:And to your point, there was active comparison versus placebo in the other 2 trials. It is something to think about. For me in practice, I haven’t completely synthesized all these data. However, I think for me, for those who are already on bevacizumab and I’m seeing benefit and they’re not having too much toxicity, why not just put it together and give her the highest chance? On the other hand, I haven’t started bevacizumab in my other 50%.

Bradley J. Monk, MD, FACOG, FACS:And you’ve got PRIMA.

Thomas J. Herzog, MD:Then I go with PRIMA, or I could use another strategy and start with PARP upfront with chemotherapy if I wanted to do that, and then that would be the VELIA trial strategy.

Bradley J. Monk, MD, FACOG, FACS:I don’t think this is true, but I’ve heard some people say that PAOLA-1 is going to cause more bevacizumab use. Do you think that’s true? I don’t think it is.

Thomas J. Herzog, MD:I don’t know if it’ll move the needle a whole lot on that.

Bradley J. Monk, MD, FACOG, FACS:I don’t either.

Thomas J. Herzog, MD:It might a little bit.

Bradley J. Monk, MD, FACOG, FACS:But people have their biases already.

Thomas J. Herzog, MD:I think the only thing is the high-volume treaters are probably not going to change a lot because they’ve already looked at these data. The low-volume treaters haven’t really thought about bevacizumab being approved, because it was not the noisiest of approvals.

Bradley J. Monk, MD, FACOG, FACS:Right.

Thomas J. Herzog, MD:Owing largely to the fact that it was the third approval and it had been approved in Europe, so it leaked out almost in the United States.

Bradley J. Monk, MD, FACOG, FACS:And the biosimilars were coming.

Thomas J. Herzog, MD:Yes, there’s a lot going on there in terms of promotion and so forth. So given the people who are not as familiar with the literature, it brings to mind that, “Oh, you can use this upfront, and a lot of experts are using it in certain patients. Maybe I should be thinking about what those patient characteristics are and I should use it in my practice.”

Bradley J. Monk, MD, FACOG, FACS:Yes. And so then our theme is HRD [homologous recombination deficiency]-positivity. In PAOLA, if you had an HRD-positive patient, which now after you’re done with the 6 cycles you have those data, it increases from 16 to 28 months. I like that I start the bevacizumab, and if she’sBRCAor HRD-positive, I layer olaparib on. And if she’s not HRD, she probably doesn’t need it. What do you think of that?

Thomas J. Herzog, MD:I think, again, looking at these medians, looking at the numbers you’re using, they’re incredible, right? And that’s what’s so great about having all this new ammunition from ESMO.

Bradley J. Monk, MD, FACOG, FACS:Well, that’s the only way we’re going to justify the cost and the toxicity.

Thomas J. Herzog, MD:That’s right.

Bradley J. Monk, MD, FACOG, FACS:If patients are really having long-term benefit, because we have to justify again the cost and toxicity.

Thomas J. Herzog, MD:That’s right. And it’s still hard to exactly pin down who these patients are versus the PRIMA population. For the high-risk group, use PRIMA, no doubt, based on looking at the control arm. But then again, you’re only up against placebo. How do you look at those number of stage IV patients? So I think there’s a lot to digest there, I really do.

Transcript edited for clarity.