Paul A. DiSilvestro, MD, on Ovarian Cancer: New Data on Olaparib in Newly Diagnosed Disease

The objective of the SOLO1 trial was to determine the role of maintenance elaborate versus placebo in the treatment of women with advanced ovarian cancer in a BRCA a mutation. This trial completed enrollment in 2015, and at the initial presentation in 2018, demonstrated a 70% risk reduction in terms of death or progression versus placebo. A follow-up survival analysis in 2020 demonstrated that the median progression-free survival for the olaparib arm was 56 months, compared to 13 months in the placebo arm, again, confirming the benefit at that time. Nearly half of women were progression free at five years, versus 20% in the placebo arm. The overall survival analysis, which we presented, was performed at the seven-year time point, which is a clinically-meaningful time point in ovarian cancer survival. There were 391 women in the trial, they were randomized two to one to maintenance olaparib versus placebo and treated for two years. I will note that despite only a two-year treatment cap, we have seen maintain benefit beyond that in the earlier analyses. In this analysis, we devised something called an alpha spend, which is really a statistical way of saying, "How much are you willing to invest in a time point which was not your pre-specified overall survival endpoint?" So in this trial, the pre-specified overall survival has been determined to occur at 60% data maturity. In this trial, we're at 38% data maturity, so our alpha spend was .0001, or that we needed to be less than that for a p-value to determine statistical significance. So from a result perspective, maintenance olaparib has not yet reached its overall survival median. The median overall survival for the placebo arm was 75 months, and our hazard ratio was .55, which is a 45% reduction in risk of death at seven years after the last patient was randomized. If you look at it from a clinical perspective, 67% of women are alive seven years after their initial diagnosis, versus 45% in the placebo arm. In terms of the p-value, the p-value was 0.0004, which does not meet the level of statistical significance generated by our earlier alpha spend. Other analyses that we perform include something called time to first subsequent therapy, which is really a proxy for progression-free survival. So if you look at the women who are surviving in this trial, they're not only surviving, but the majority are surviving without actually having had a subsequent therapy, meaning they've had nothing beyond their initial treatment. Time to second subsequent therapy, which is really an indicator of, "Do you benefit beyond your first subsequent therapy?" And that was shown to be true, as well, favoring maintenance olaparib. We didn't see any new safety signals. We've been following the risk of MDS or AML, as well as new primary malignancies for the entirety of the trial, along with survival. And really, there's only been one new case that MDS or a AML in each arm, and new primary malignancies remain well balanced. There are no new adverse event signals, as well. So in summary, the SOLO1 trial demonstrated that maintenance olaparib provides a clinically meaningful benefit for women with advanced-stage ovarian cancer in a BRCA mutation. What does that mean for our practice of G1 oncology? It means that we need to be aware of germline and somatic BRCA status. We need to know that information so that when we make choices of maintenance therapy for our patients, we can utilize beneficial drugs, such as olaparib, to help improve their overall outcomes.