Practical Implications for Treatment Strategies in Advanced Ovarian Cancer - Episode 2

Biomarker-Driven Frontline Ovarian Cancer Treatment

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Bradley Monk, MD, FACOG, FACS: I thought we could begin by reviewing these 4 key papers and approvals. The first was bevacizumab in June of 2018. Michael, tell us about that.

Michael J. Birrer, MD, PhD: I would start out by saying it’s the granddaddy of the trials because, as you know, it opened all the way back in 2008, and it was the first trial that brought a biologic agent and a targeted agent into the treatment of ovarian cancer. It was a randomized phase 3 trial with 3 arms. The control arm was carboplatin-paclitaxel. The second arm was an experimental arm that utilized bevacizumab and concurrent treatment with a placebo maintenance portion. The third arm, which was experimental, was concurrent bevacizumab with chemotherapy and then a maintenance phase with bevacizumab going about 15 months, 22 cycles.

As you know, when the trial closed and was analyzed, there was a statistically significant prolongation of PFS [progression-free survival] comparing that third arm, concurrent and maintenance, to the control arm. The second experimental arm, which was just concurrent therapy, had no difference. This prolongation of PFS was about 6.2 months, which is in the indication; it was highly statistically significant. It’s interesting to note the hazard ratio is 0.71, which we were excited about, which pales now in comparison to PARP inhibitors.

There’s been a recent follow-up study for the long-term evaluation of this trial by Muneesh Tewari PhD, MD, and his colleagues, and that showed that the original observations were true. There is no overall survival [OS] advantage, but a subset analysis looking at some high-risk patients, like stage IV, suggested that they may have benefited the most and had a survival advantage.

The only other comment I’ll make on this is that we could use a biomarker to identify those patients who benefit. We’ve done CD31; there’s IL-6 [interleukin-6] data. None of it’s validated, so at present, we can’t identify the patients who specifically benefit from use of bevacizumab.

Bradley Monk, MD, FACOG, FACS: It was a breakthrough, to your point, and it was the first targeted therapy approved in ovarian cancer. It’s interesting that it was published and approved in Europe in 2011. Leslie, why do you think it took 7 years between the EMA [European Medicines Agency] approval to the US approval?

Leslie Randall, MD, FACOG: That’s a good question because it was set up as a registration trial. The intent from the beginning was to file; it just wasn’t an impressive enough hazard ratio. Back then, we were looking to hit the OS mark. In that interim time, that’s when we had talks with the FDA that OS was not the best end point in ovarian cancer, and the earlier the line of therapy, the more difficult it is as an end point.

Bradley Monk, MD, FACOG, FACS: That’s the key point. We had to come to an agreement with the regulatory agency that overall survival was not possible because patients got lots of lines of therapy. In other words, the post-progression survival was long, and as Dr Birrer said, as long as the PFS benefit was big and meaningful, not too toxic, and convenient—which every-3-week intravenous bevacizumab is—that they would give us an approval. That was excellent, but as you said Michael, no biomarker and a hazard ratio of 0.6, 0.7, OK, but now? Go ahead Shannon; we now have a biomarker and a big difference in the unprecedented, same year, December 2018 approval, of SOLO-1. Tell us about that.

Shannon N. Westin, MD, MPH, FACOG: That’s right. It is absolutely biomarker driven. This was a randomized controlled trial of patients in the upfront setting who had advanced-stage disease at the beginning, either high-grade serous or high-grade endometrioid. Importantly, they had to have a BRCA mutation. That could be either germline or somatic, although as we all know, the majority of these patients did have a germline mutation. There were 2 patients who had a somatic mutation.

These patients, after they had response to their upfront platinum-based chemotherapy, were then randomized to either receive olaparib maintenance versus placebo, and they were randomized 2:1. There are a couple of important points here. One is that the patients received that olaparib or placebo-maintenance for 2 years, unless there was unacceptable toxicity, and then were followed. The primary end point was progression-free survival. What we saw was an impressive reduction in the risk of progression, with a hazard ratio of 0.3. To your point, we were excited about the hazard ratio of 0.7, but now here we were with a 0.3, a 70% reduction in the risk of progression.

What was cool about this trial is that they kept following the progression out. A year after the majority of those patients had stopped treatment, 60% of the patients on the olaparib arm were progression free compared to 26.9% who were progression free at 3 years who were on placebo.

It answers a couple of questions. One, when you use a targeted maintenance, it works. Two, you can stop it. You don’t necessarily have to continue it because what we see is a beautiful flattening of the curve. We don’t know if it is going to yield an overall survival benefit; that’s the next big question. It’s going to take a while to get that answer, but certainly impressive data that led to an FDA approval for this drug.

Bradley Monk, MD, FACOG, FACS: A hazard ratio of 0.3 and 3 years of improvement in progression-free survival is transformational. Matt, was that enough for you? Did that change your practice?

Matthew Powell, MD: Yes, I think so. When you look at these patients who have a biomarker-driven therapy with this, it has impressive changes. It’s definitely driven what I would consider the standard of care for these patients.

Bradley Monk, MD, FACOG, FACS: What about the risk of MDS [myelodysplastic syndrome]? For patients, maybe it’s not such a great idea after all.

Matthew Powell, MD: Certainly, the rate remains low. Predictively, that 1% range is certainly something to consider, but when you see such a difference in PFS, we can feel quite confident that they’re improving the quality of patients’ lives, and they’re likely living longer.

Bradley Monk, MD, FACOG, FACS: To your point, advanced stage ovarian cancer is almost always lethal, so it’s all about the risk-benefit ratio.

Transcript Edited for Clarity