The Impact of PAOLA-1 on Frontline Treatment of Ovarian Cancer

Bradley Monk, MD, FACOG, FACS: Leslie, we had GOG-0218, no biomarkers, it was a start. Now we have SOLO-1, biomarkers. It’s sensational, but it was only in a quarter of the patients. Tell us about what PRIMA did to expand the opportunity.

Leslie Randall, MD, FACOG: SOLO-1 was exciting, and unprecedented, but that was the problem. That only applied to a quarter of your patients. Giving a survivor talk at [The University of Texas] MD Anderson [Cancer Center] where Shannon is, I had a patient ask me, “What about the rest of us?” He said, “This BRCA thing is great, but what about me, Dr Randall?” I never forgot that patient because it’s true; you need to be able to expand this to some of our non-BRCA patients. PRIMA did just that.

Niraparib had already done that in the recurrent setting of NOVA, but PRIMA was the frontline trial; it was randomized, phase 3, placebo controlled. This was an interesting trial in that it had entered the worst patients: stage III/IV, high-grade serous or endometrioid who had stage III, primary debulked with visible or residual disease, either neoadjuvant or inoperable, so really high-risk disease and all stage IV.

The patients had to have had complete or partial response to chemotherapy, and they could then be randomized 2:1 to niraparib versus placebo. All biomarker populations were eligible, and this is before we knew the SOLO-1 data, or likely BRCA patients would have been excluded from this trial, but they were not. I thought this trial would be negative because of the high-risk population, but it was not. It did show a benefit: a hazard ratio of 0.62 for the overall population.

If you then broke that down into the biomarker group, you saw some more granularity: the HRD [homologous recombination deficient] group had a 0.43 hazard ratio. If you then looked at the BRCA wild-type HRD, there was a 0.50 hazard ratio. I was shocked to see these data when this was presented at ESMO [the European Society for Medical Oncology annual meeting] because I did not expect to see this degree of benefit in this higher-risk population.

Bradley Monk, MD, FACOG, FACS: One of the things that SOLO-1 did was it was a GOG [Gynecologic Oncology Group] study: a non-CTEP [Cancer Therapy Evaluation Program] study; GOG-0218 was an NCI [National Cancer Institute] study. What PRIMA did was very collaborative, not only with the GOG beyond the government, but with our European colleagues as well. That’s the new standard moving forward as these are now international trials with the European Network of Gynecological Oncological Trial Groups [ENGOT] and the GOG. The GOG and all of us here on this call on Webex are leaders in both organizations. But the GOG partners is a sponsored, collaborative effort, and that’s what this did.

If you looked, Leslie, from the first patient enrolled in PRIMA to the FDA approval on April 29th, it was 37 months. We, you, our audience, changed the standard of care in ovarian cancer in all comers in 37 months. You said, Michael, GOG-0218 took more than 10 years from the time that the study started until it got FDA approval. That was important.

Let’s talk about the rest of the population. I liked your analogy: “Well what about me?” HRD is doubling the opportunity from BRCA to the biomarker. We’ll talk about the biomarker, but there’s a chance to double it again for all comers, from 25% to 50%, but we want 100% of the opportunity. The question now that we’ve heard about beyond BRCA and bevacizumab, Matt, is why don’t we add them both? Well, indeed, that study was also published in the New England Journal of Medicine with PRIMA in December of 2019. In addition to being published, it was also presented at ESMO, and it led to FDA approval on May 8th. Tell us, Matt, about PAOLA-1.

Matthew Powell, MD: PAOLA-1 took the best of both worlds as you said: the 2 targeted therapies, adding them to carboplatin-paclitaxel. The European study was an investigator-initiated trial, so it was different than the setup you just talked about. Over 800 patients were randomized in a 2:1 fashion to get olaparib plus bevacizumab versus placebo plus bevacizumab, and that was up to 15 months of bevacizumab and then 2 years of the olaparib at that 300 BID [twice daily] dosing, and it had impressive results.

If you look at the intent-to-treat population, the hazard ratio was 0.59. If you focus just on what got FDA approved, the HRD tumors had a ratio of 0.33. It was an amazing difference that we’re seeing, and we’re quite excited. Tolerability was the key for this. We’re well versed in the use of bevacizumab, and there was no unique toxicity signal seen with that combination. It is easy to do, and patients tolerate it well. There were at least additive effects for the 2 targeted therapies and maybe even a little more; it’s hard to tell for sure.

Bradley Monk, MD, FACOG, FACS: So 37.2 months at the median for half of patients with newly diagnosed advanced ovarian cancer: 3 years. We used to follow our patients every 3 months for 2 years because they almost all recur by 2 years. That doesn’t work anymore. Now you need to follow your patients very carefully for a long time because the recurrences now have been prolonged: 3 years at the median. That’s the best number ever, right Matt?

Matthew Powell, MD: Yes, it’s up there, and it shows. There was a group of this population: 20% had BRCA1 and a little less than 10% had BRCA2. It’s a general population that we tend to see in our office, so it’s exciting. You see these great outcomes in not just a special population, but a general population.

Bradley Monk, MD, FACOG, FACS: As I said though, you only use the combination when you start with bevacizumab. Michael, you presented us GOG-0218. Do you think this is going to increase the use of bevacizumab because of this wonderful combination result, at least in the HRD-positive subset?

Michael J. Birrer, MD, PhD: That’s a good question. I feel like it’s back to the future. We had years with carboplatin-paclitaxel. No selection of patients; everybody got the same thing. We then ushered in bevacizumab and PARP inhibitors, and we said we were giving precision medicine. Now with PAOLA and PRIMA, the question is, is everybody going to get everything or how are we going to stratify patients? It’s a good question.

In Europe they use a lot of bevacizumab, so they’re likely to add olaparib to a lot of those patients. In the United States, because of what we talked about with [Muneesh] Tewari’s, [PhD, MD,] paper and ICON7, we tend to give bevacizumab to the high-risk patient: residual disease, suboptimally debulked. I don’t think this is going to change that fairly rapidly; it’s going to take some time. That’s my personal feeling.

Bradley Monk, MD, FACOG, FACS: What do you think Shannon? More bevacizumab with PAOLA-1?

Shannon N. Westin, MD, MPH, FACOG: Well I will say, coming from an institution that was slow on the uptake of bevacizumab, [The University of Texas MD Anderson Cancer Center], I definitely see more use across my partners. I like to stratify who I’m giving bevacizumab to based on their overall status, if they have ascites, and those kind of things. I’m leaning more toward thinking about it because those results are impressive, and you want to give the patient the best opportunity up front. We know that’s our best chance, so I do think that we’re going to see a slow uptick.

Transcript edited for clarity.