Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University; Robert L. Coleman, MD, MD Anderson Cancer Center; Gottfried E. Konecny, MD, University of California, Los Angeles; Katie Moore, MD, University of Oklahoma; Matthew A. Powell, MD, Washington University in St. Louis
Bradley J. Monk, MD: We have 3 PARP inhibitors approved now—3. The first one, approved December 19th, 2014, was olaparib. That’s probably our most familiar medication. That is a capsule, 400 mg twice daily, based on accelerated approval from a trial of 137 patients, a 34% response rate, and 7.9 months duration of response. And then, the confirmatory trial, which we call SOLO-2—you were eager to tell us about it, go ahead. Tell us about SOLO-2 as the second-line maintenance.
Gottfried E. Konecny, MD: Well, this was a large study: approximately 300 patients, who had either a partial or complete response to platinum-based chemotherapy and then went on to receive maintenance olaparib. These were all patients with germline BRCA mutations, and the study confirmed the improved progression-free survival as seen in Study 19, the preceding study. But I think at this year’s meeting, we saw 2 interesting presentations. One was that they, of course, showed the data that were initially presented at SGO. But in addition, they did a report on patient-reported outcomes, which was always the question.
We were involved in making PFS a valid endpoint for studies in recurrent disease, but you need to have other secondary supportive endpoints like time to second subsequent treatment or PFS2, which are now becoming standard in trials and patient-reported outcomes. This was a very thorough analysis of the FACT-O and the TWiST, time without symptoms of either toxicity or disease. It clearly showed that factoring in the toxicity of the drug, there was a significant improvement in PFS in these patients getting maintenance, and there’s a clear benefit very consistent with the niraparib data.
Bradley J. Monk, MD: After platinum response, BRCA-mutated, there was a hazard ratio of 0.30. Increasing the control arm, it was 5.5 months median PFS with placebo to 19 months median PFS with the active treatment. That’s unprecedented, a hazard ratio of 0.30 and a tripling of the PFS, and now quality of life benefit. Katie, what’s the tradeoff? Tell us about the side effects of olaparib.
Katie Moore, MD: So, with olaparib, surprisingly, the tablets and the capsules don’t look that much different to me, which I’m surprised about.
Bradley J. Monk, MD: They tried to develop the tablets with a similar toxicity profile, even though they’re different doses.
Katie Moore, MD: Absolutely, even though they’re different doses. I really thought we were going to see less GI toxicity, because the pill burden was so much less with the tablets, but it looks very similar. So, with class effects of PARP inhibitors and olaparib in particular, you see nausea in about 65% of patients. The vast majority is grade 1 or 2. You see diarrhea in about 25%—again, mostly grade 1/2— fatigue in 60%, and dyspepsia, mainly GI side effects. And then, you do see some hematologic side effects, which can differ between the PARP inhibitors. Anemia seems to be pretty consistent in olaparib: grade 3/4s are only about 11%. The confidence intervals probably overlap, but it looks a little lower. With platelets, grade 3/4s are about 5% to 6%, and neutropenia is similarly less than 10%, grade 3/4. You do see drops more frequently in lower grades, but it tends to be less consequential on therapy.
Gottfried E. Konecny, MD: But, because of these side effects, we were always worried to put someone on a maintenance therapy, on a daily schedule with all these side effects. It’s not worth the improved PFS, but doing what they call a TWiST analysis, where you subtract the time that you have with symptoms from the PFS—despite subtracting that, these were grade 2 toxicities, so we’re not talking grade 3 or grade 4. Grade 2 is not considered serious, but it is awful if you have it every day.
Katie Moore, MD: It’s meaningful.
Robert L. Coleman, MD: Absolutely.
Gottfried E. Konecny, MD: And despite that, there was a highly significant improvement. So, it’s an important study that added to our understanding.
Robert L. Coleman, MD: That may be the most important finding of all this, because I think we’ve had good evidence from our phase II experience and our single-arm trials across the past 8 years that these drugs work. They work as maintenance; they work as treatment. But the context is so important, and that was the missing piece. You’re exactly right, the thing that gets missed are the grade 1/2 toxicities that are annoying, and that was clearly identified.
Bradley J. Monk, MD: So, the approval in Europe is as maintenance; the approval here is as treatment after 3 prior lines and with a germline mutation. This has obviously been submitted to the FDA, and we’re hoping it will get a maintenance indication. Rob, tell us what the combinations are now with olaparib.
Robert L. Coleman, MD: There are a lot. Actually, why don’t we just do classes because there are so many? The context here is how we make PARP better or how we overcome PARP resistance, so those are the classes. There’s angiogenesis, targeted therapy after hypoxia. We’ve got immune therapy, targeting, potentially, greater mutational load. We’ve got DNA checkpoints. So, this is going after alterations within the DNA damage response pathway. We’ve got p53-targeted drugs. We’ve got other agents within the pathway, cyclin kinase inhibitors. We’ve got Chk1, Chk2, ATR, ATM, and it just continues to expand from there, because we’re learning more about what it is that’s critical in these processes.