Aaron Tallent, Interviewer: Can you describe the SOLO1 trial and the most clinically significant findings?
Paul DiSilvestro, MD: So the SOLO1 trial enrolled just shy of 400 women with advanced ovarian cancer in a BRCA mutation who had initial clinical response to surgery and chemotherapy in a 2:1 randomization to a drug called Olaparib, which was a PARP inhibitor, versus placebo. And that was a two year prescription of that regimen, after completion of their primary treatment. Patients were then followed for the initial primary endpoint progression-free survival with a series of secondary endpoints, including overall survival, which was the focus of my presentation recently at the ESMO meeting. So the trial had previously concluded based on the initial analysis that giving maintenance Olaparib for two years, yielded a 70% reduction in the risk of progression or death versus just maintenance placebo. And so this was now basically a look-see, for lack of a better term, at seven years after the last patient was randomized. So that would be actually five years since the last patient concluded their therapy. So what it showed us is that maintenance Olaparib maintained that benefit well beyond the two years of treatment with a 45% reduction in the risk of death seven years after the last patient was randomized. So, a real clinically meaningful impact.
Tallent: How do you compare these results to the results from the PAOLO1 trial?
Dr. DiSilvestro: So it's interesting. We're always hesitant to do cross-trial comparisons, especially since sometimes the patients aren't exactly the same when they go into these trials. I think if you look at the relative impact of the PAOLO1 regimens on patients in three categories, you have the patients who have a BRCA mutation akin to the SOLO1 population. Those people had a very profound effect on survival, not to the exact extent that SOLO1 did, but again, different patients, more advanced stage patients, patients with some poor prognostic indicators. Those who had a homologous combination deficit, which is basically a molecular impact of changes in the tumor. Similar to that, that we see with BRCA, again had a similar benefit. Those patients who lacked either of those descriptors really didn't see too much of an impactful benefit from the combination of Olaparib and Bevacizumab versus standard Bevacizumab consolidation. So similar benefits, perhaps not to the degree, but again, there's always the hazards of cross-trial comparison.
Tallent: Did these long term studies tell us anything more about PARP inhibitor side effects?
Dr. DiSilvestro: So the interesting thing here, and I break it down to a couple of different things. One is what we call safety signals, meaning, are there things that could happen in the long run that you weren't aware of when you started? And two areas of concern for us are something called MDS or myelodysplastic syndrome or acute myelogenous leukemia and the other one is new primary malignancies and new cancers developing. And so if you look at the arms, the incidence of the MDS and AML is low and well balanced. And since the initial presentation four years ago, there's been one more case of that diagnosis in each of the arms. So again, remaining well balanced in terms of new primary malignancies. Again, those rates are well balanced. And for women who have a BRCA mutation, breast cancer is their highest risk. And that pans out in the data that we see. So no change in that.
The 'other then' issue is "Well, what about the drug itself, direct causes? What can they do right to a patient then and there? Well it's five years since the last patient got in. And so that adverse event profile did not change because much of that is treatment related effect during treatment or soon afterwards. So we didn't see any new signals there.
Tallent: What do you make of the contrast between these first line results and the results of ARIEL4 presented in the same session?
Dr. DiSilvestro: Well, I tell you that's really put out a lot of news out there. I had the opportunity to watch the ARIEL4 presentation. And if you've looked at the news, as it relates to PARP inhibitors, you've begun to see this withdrawal of approvals. And it's not necessarily the FDA withdrawing. I think it's discussions with the FDA and then basically a voluntary withdrawal. So Niraparib had an indication for whatever we call HRD positive patients in the fourth line that just got withdrawn. Olaparib had a third line, BRCA mutated, single agent indication, removed. Rucaparib, the same thing. So the PARP inhibitors that we use in common ovarian cancer, really the focus swings towards those maintenance approaches, be it first line or second line maintenance. And we've really seen a pullback on those. And it really is sort of looking at long-term data from these studies and in comparison to standard agent chemotherapy.
And that's why you follow these studies along, right? It's not like when we get that first progression free survival indicator and say, "Hey, everything's great". You really got to watch it and see, does this pan out, do we see a continuing benefit or do we actually see that at some point in time, maybe we're not doing the right thing.
Tallent: Which other gynecologic cancer studies presented at ESMO did you find most clinically significant?
Dr. DiSilvestro: Well, I think the one was, I believe it was the ATALANTE study. Don't swear to me on the pronunciation of that one. And that again was looking at something that we've looked at in other studies, which is the role of immunotherapy in ovarian cancer. I think a lot of folks have very high hopes about that and have basically found that the addition of immunotherapy to frontline treatment has not yielded a progression free benefit. We just haven't seen that if you look at the survival curves of the arm that contains the immunotherapy and the arm that contains the placebo agent, they're overlapping. It's like you just took one marker and drew one line. And so we're just not seeing the separation. So it really just points us back to the fact that we need to understand better the role of immunotherapy and ovarian cancer. How do we integrate it? Is it dual agent? Do we have to, in some ways, prep the tumor to be more susceptible to these agents? And that was to me important.
Tallent: Well, this is great. I appreciate it.
