Pivotal Trials in the Realm of Ovarian Cancer

Shannon Westin, MD: Let’s get into a little more detail about each trial. This is SOLO-1. This was a true maintenance therapy after first-line chemotherapy. All patients had a BRCA1/2 mutation and had a response to therapy. They could have either neoadjuvant or up-front surgery. They were randomized 2-to-1 to olaparib versus placebo, and the primary end point was investigator-assessed progression-free survival. Of note, they received the olaparib for only 2 years, 24 months. There was a clear benefit in progression-free survival with a reduction in the risk of progression of about 70%. There are a few things I want to highlight in this slide that always make me get excited. One is that they got treated for only 2 years, yet the curve continues on, and the 3-year progression-free survival is improved at 60% in those patients who received olaparib versus 27% for the patients who got the placebo.

The second thing is that this is a population we consider to be our good actors. These are the patients with BRCA mutation, who tend to respond very well to chemo, and who had better overall survival when compared with patients without. For this population, at 3 years, only 27% were progression free. This helps me feel confident that we do, in fact, need to use maintenance to be able to help impact these patients. At this point, we do not have a way to identify those patients who would be without progression in the absence of a PARP inhibitor. Those are the exciting things about this; we’re still waiting on overall survival data. It does seem like there’s a flattening of the curve there that may yield a survival benefit, but it’s too soon to tell.

This is just a snapshot of subgroup analyses that were done around progression-free survival that shows that the addition of olaparib was beneficial regardless of CA-125 [cancer antigen 125] level, type of BRCA mutation, the age of the patient, the stage, and all those types of things.

Whenever we’re talking about maintenance or any treatment, we want to talk about adverse events. The adverse events we saw in the SOLO-1 trial with olaparib were consistent with what we’ve previously seen in PARP inhibitor trials, both in treatment and in secondary maintenance. A lot of GI [gastrointestinal] adverse effects, which are class effect: nausea and vomiting. I think this group would agree that those are mainly going to be in the first few months, and that once you get through that, you can see quite a reduction in those issues. We also see bone marrow effects, neutropenia, thrombocytopenia. I’ll call your attention to the bottom of the slide. The discontinuation rate in the SOLO-1 trial was about 12%, which is consistent with most PARP inhibitor trials. A majority of these patients can get these adverse events, and those adverse events can be mitigated and keep that patient on an appropriately effective therapy.

The PRIMA trial was similar but different: a randomized, controlled trial. This was a more high-risk population, although it was in all comers. They allowed anybody regardless of their BRCA status, but they did select for a more high-risk group, both stage IV as well as patients who had residual disease and stage III. They tried to select a more high-risk population to get an early signal and to make sure this treatment worked. There was a 2-to-1 randomization between the niraparib and placebo, and the primary end point was progression-free survival. This is just the demographics, to highlight: about 36% of the patients were stage IV, and a large proportion of them had neoadjuvant. Two-thirds of the patients had neoadjuvant chemotherapy, which is reflective of this high-risk group.

Here are the results in the overall population: this is all comers. There was about a 40% reduction in the risk of progression with the addition of niraparib, about a 4- to 5-month overall difference. When we started teasing it out by subgroup, you can start seeing the impact of the biomarker. This was a planned analysis, a planned primary analysis of the HRD [homologous recombination deficiency]–positive patients, a 60% reduction in the risk of progression in that HRD subgroup. You can see an impressive difference in the median progression-free survival as well.

The table on the bottom gives a little more teasing out, looking at BRCA-mutant where we see the 60% reduction; HRD-positive BRCA wild type, which is about a 50% reduction; and then HR [hormone receptor]–proficient patient population was about a 30-something-percent reduction in the risk of progression, so this is similar to what we’ve seen in other PARP inhibitor trials. There’s definitely an impact of having the presence of a biomarker but still some activity in that HR-proficient group. I’ll be interested to see what my colleagues think about that.

This is another forest plot looking at progression-free survival, teasing out the positive impact of niraparib in the groups is irrespective of that biomarker but definitely the biggest impact in those patients with mutation or HRD.

Then we have some overall survival data, although it’s a little early for PRIMA, but there is a trend potentially toward an improvement in overall survival in the HR-proficient group. It will be interesting to see if that’s borne out by later data. This did get a recent FDA approval for all comers with advanced ovarian cancer after response to their first-line platinum-based therapy.

The PAOLA data: this was an interesting trial that took any patient who had gotten chemotherapy with bevacizumab and then randomized them after response to therapy to receive either bevacizumab alone or bevacizumab in addition to olaparib. The patients were continued on the PARP inhibitor for 2 years, and the primary end point was progression-free survival. In the all comers’ intention to treat, there was a statistically significant difference, about a 40% reduction in the risk of progression with the addition of the olaparib to the bevacizumab in that all-comers group. When they teased out in the prespecified subset analyses, the biggest impact was on those patients who either had a BRCA mutation or had HRD in their tumor, and there was minimal benefit along the population that was HR-proficient.

They went in, and we now have an FDA indication for olaparib and bevacizumab in HRD-positive tumors. That can be defined either as BRCA mutation in germline or the somatic tumor or if they have genomic instability with 1 of the current available testing platforms. Dr [Thomas] Krivak is going to talk about that going forward.

We’ve got this set of guidelines for primary systemic therapy. This is what we do with chemotherapy. You can see that platinum-based chemotherapy reigns supreme with surgery, either before or after chemotherapy in the neoadjuvant setting, and there are a number of different regimens you can potentially utilize. Once we get through that, then we get into what’s been recommended for maintenance. You can see that, from the standpoint of the NCCN [National Comprehensive Cancer Network], they recommended niraparib for any BRCA wild type or unknown after response to therapy, and then niraparib or olaparib for germline and somatic BRCA mutations. These guidelines came out before these approvals, so there’s a subset, a comment about the HRD testing and whether you want to use that, and they do mention it. It will be interesting to see if these guidelines are revised at all now based on the indication and the approval that just came out about a week ago.

Transcript edited for clarity.