Phase III Shows Benefit With Olaparib in Platinum-Sensitive BRCA+ Relapsed Ovarian Cancer

Richard T. Penson, MD

Richard T. Penson, MD

According to topline findings from the multicenter, open-label, phase III SOLO3 trial, the overall objective response rate (ORR) was 72% with single-agent olaparib (Lynparza) versus 51% with chemotherapy in patients with platinum-sensitive, relapsed, germlineBRCA-mutant ovarian cancer who were previously treated with at least 2 chemotherapy regimens. Further, in patients with only 2 prior lines of chemotherapy, the ORR was 85% with olaparib compared with 62% with chemotherapy.

The PARP inhibitor olaparib was granted an accelerated approval in December 2014 for the treatment of patients with advanced ovarian cancer who had received at least 3 or more prior lines of chemotherapy and harbor aBRCAmutation. Theseconfirmatory data, presented at the 2019 ASCO Annual Meeting,support the full approval of olaparib in this setting. Olaparib has previously been approved as a frontline maintenance in ovarian cancer, while 2 other PARP inhibitors are approved in the field as well.

“[PARP inhibitors] are not cost-effective therapies, but the fabulous strength about olaparib is that it has a really good toxicity profile, the rate of data, and far more patients have had it than the other PARP inhibitors,” said Richard T. Penson, MD. “Now the previous concern of a 34% response rate is an 85% response rate; I think the efficacy really is part of that encouraging profile for a great drug.”

Investigators enrolled 266 platinum-sensitive patients with relapsed high-grade serous or endometroid ovarian cancer, primary peritoneal, and/or fallopian tube cancer with germlineBRCAmutations, who had at least 2 prior lines of platinum-based chemotherapy. Patients in the SOLO3 trial were randomized 2:1 to receive either olaparib or physician’s choice of a single-agent, non-platinum chemotherapy.

Overall the median progression-free survival (PFS) was also improved in the olaparib arm with a median PFS of 13.4 months versus 9.2 months (HR, 0.62; 95% CI, 0.43-0.91;P= .013).

Overall, 50% of patients in the olaparib arm had at least 1 grade ≥3 adverse event (AE) versus 24% in the chemotherapy arm. The most common grade ≥3 AEs included anemia, neutropenia, fatigue/asthenia, thrombocytopenia, nausea, vomiting, and abdominal pain with olaparib.

Of special interest, 4 patients in the olaparib arm developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) compared with 3 patients in the chemotherapy arm.

In an interview withTargeted Oncology,Penson, clinical director, Medical Gynecologic Oncology, Massachusetts General Hospital, discussed the significance of the findings recently presented for the SOLO3 trial in patients with platinum-sensitive, relapsedBRCA-positive ovarian cancer. He also highlighted the role of olaparib in comparison to other FDA-approved PARP inhibitors in the ovarian cancer space and how it is being used in other ongoing trials.

TARGETED ONCOLOGY:Could you share some background to the SOLO3 trial and the significance of these findings in terms of the data from SOLO1 and SOLO2?

Penson:SOLO3 was the third of the SOLO studies of olaparib in ovarian cancer, and it demonstrated a superior ORR, supported by a good PFS in patients with platinum-sensitive germline BRCA-mutated ovarian cancer. The background is that the hope for this first-in-class PARP inhibitor was going to be a small 97-patient study comparing 2 doses of the [olaparib] capsule with pegylated liposomal doxorubicin. People were so excited about this new agent that we thought with a quick phase II trial, everything was done.

In these patients sensitive to DNA-intercalating drugs, pegylated liposomal doxorubicin performed well; the study showed equivalency. They are both good agents. The whole program was put back years by that, so we now have much more complicated things, [such as] 6 trials put together for [patients with] 3 or greater prior lines of treatment, [demonstrating] a 34% response rate. This did not have an FDA approval, but how good is the drug? In SOLO1, there was staggering improvement in outcome. You get olaparib as a switch maintenance therapy or first-line therapy, and PFS improves from 1 year to more than 3 years with a hope of cure. SOLO2 was a solid endorsement; it’s effective in platinum-sensitive recurrence. Now SOLO3 just adds to that in terms of being a really effective agent. As third-line therapy, there is an 85% response rate, so it’s very exciting.

TARGETED ONCOLOGY:What do you think these data mean for the future of olaparib?

Penson:Essentially, it won’t mean anything more in terms of the third-line and beyond; we know it’s effective. What they mean is that we should be moving effective drugs upfront to try and get cures for patients. Every single patient should getBRCAgene testing, probably both inherited germline testing and acquired tumor/somatic gene testing. There was a staggering report that showed only a third of American women in Georgia and California are getting gene tested with ovarian cancer, so it’s not so much that we know it works and we know our patients with aBRCAmutation should get it; we have to find every patient who harbors aBRCAmutation so that there is a maximum impact for this new class of agents.

TARGETED ONCOLOGY:What long-term safety data were noted in SOLO3?

Penson:There were no new safety signals in SOLO3; we had the same sort of toxicities, [including] gastrointestinal, constitutional, and hematologic [toxicities]. There was nausea, some vomiting, fatigue, and anemia. People worry about MDS and AML; that happened 2% of the time [in the olaparib arm], but it actually happened 4% of the time in the chemotherapy arm. There remains no clear association between the PARP inhibitors and this awful complication of chemotherapy. We think that AML relates to harboring aBRCAmutation, sensitivity, and to chemotherapy agents. We don’t know from SOLO1 since it’s too early, but both SOLO2 and SOLO3 saw lessBRCAmutations with PARP inhibitors. It’s really very exciting. In fact, there’s actually enough excitement that we are seriously thinking about prevention studies with PARP inhibitors, which had previously been put on hold because of the concerns about that serious toxicity.

TARGETED ONCOLOGY:With 3 PARP inhibitors approved, what sets olaparib apart from the others?

Penson:Truly, they are very similar, and it’s fabulous to have choices. The old argument that a capitalistic market creates competition and drives down prices is complete rubbish. These are not cost-effective therapies, but the fabulous strength about olaparib is that it has a good toxicity profile, the rate of data, and far more patients have had it than any of the other PARP inhibitors. Now the previous concern of a 34% response rate is an 85% response rate; I think the efficacy is part of that encouraging profile for a great drug.

TARGETED ONCOLOGY:Are there any other ongoing trials for olaparib or other PARP inhibitors?

Penson:There are tons! There are actually 4 ongoing single-agent studies, which is quite amazing. What people are excited about is the combination with antiangiogenics; the ANANOVA2 trial was just presented and the bevacizumab (Avastin) with niraparib (Zejula) [combination] looks great, not just great for the patients with aBRCAmutation but great for the patients with high-grade serious cancer who are wild-type for the germline mutation. It’s about the combinations, particularly with antiangiogenics, but maybe that platform is what allows tumors to be warm enough to benefit from an immunotherapy. We are very excited about combination therapy as the next frontier.

TARGETED ONCOLOGY:Were there any unexpected findings that came out of SOLO3? Are there any other unanswered questions in the field?

Penson:Some of the unexpected things include that there was no pneumonitis seen in all of those patients, so that was 1 of the AEs of special interest. Surprisingly, there was really no worrying surprises from the study.

In terms of other trials, there’s quite a few things we’re looking at, but 1 that is probably the most important is called the OREO trial; patients who have had a previous PARP inhibitor, as long as more than 6 months had elapsed, with platinum-sensitive disease back in remission with platinum-based therapy, then switch maintenance to olaparib. It’s an olaparib versus placebo study. We are very interested in 2 things; the first is re-challenging the PARP inhibitor to see how much is the magnitude of benefit, but secondly, [we’re interested in] the biomarkers. Companion diagnostics show that unfortunately if you’ve got a reversion mutation, you’re not going to benefit, but that means patients won’t waste their time with an ineffective therapy. For the country, it means that we are using expensive therapies to their best advantage. I think OREO is important to watch in terms of what academics are interested in.

Reference:

Penson RT, Valencia RV, Cibula D, et al. Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial.J Clin Oncol.2019;37(suppl; abstr 5506).