SOLO2 is the first phase III trial of olaparib tablets as maintenance treatment, and it showed a significant benefit in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation— Eric Pujade-Lauraine, MD
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Maintenance therapy with the tablet formulation of olaparib (Lynparza) significantly prolonged progression-free survival in patients with platinum-sensitive relapsed ovarian cancer and mutations in BRCA1/2 in the phase III SOLO2 trial, presented at the 2017 Society of Gynecologic Oncology (SGO) Annual Meeting by Eric Pujade-Lauraine, MD, of the Université Paris Descartes in France.1
For patients randomized to receive maintenance olaparib, median progression-free survival by investigator assessment was 19.1 months, vs 5.5 months with placebo, which was the primary outcome. By blinded independent central radiologic review, this endpoint was 30.2 months vs 5.5 months, respectively.
Co-investigator Richard Penson, MD, of Massachusetts General Hospital, Boston, commented on the importance of the findings in an interview with The ASCO Post. “By blinded central review, where scans were carefully reviewed, progression-free survival was almost six times longer than with placebo. This is a substantial margin,” he said.
Noting the importance of this finding to clinicians, Dr. Penson added: “We were excited enough about these data to present the study at SGO instead of waiting for the ASCO Annual Meeting. We felt that waiting to present the data would not be right.”
SOLO2 Details
SOLO2 is an international randomized, double-blind phase III trial evaluating the first-in-class oral poly (ADP-ribose) polymerase (PARP) inhibitor in 295 patients with relapsed, platinum-sensitive BRCA-mutated ovarian cancer. It is the third randomized trial to evaluate outcomes for “switch maintenance” therapy in this population and the second report of an advantage in progression-free survival, Dr. Penson pointed out.
In 2012, Ledermann et al reported a progression-free survival advantage for olaparib maintenance (400-mg capsules twice daily) in 265 patients with platinum-sensitive relapsed disease in Study 19.2 The greatest benefit was seen in patients with a BRCA1/2 mutations (hazard ratio [HR] = 0.18; P < .00001). SOLO2 aimed to confirm the findings from Study 19 in BRCA-mutated patients using the newer tablet formulation of olaparib.
The study included 295 patients who had received at least 2 prior lines of therapy and were responding to their most recent platinum-based regimen. They were randomized to receive olaparib maintenance (300-mg tablets twice daily) or placebo. The primary endpoint was investigator-assessed progression-free survival; a sensitivity analysis of progression-free survival was performed by blinded independent central review.
Impact on Multiple Endpoints
Patients receiving olaparib maintenance had a significant improvement in median progression-free survival: 19.1 months vs 5.5 months (hazard ratio [HR] = 0.30; P < .0001). By blinded independent central review, the benefit was even greater: 30.2 months vs 5.5 months (HR = 0.25; P < .0001), Dr. Pujade-Lauraine reported at the meeting.
“SOLO2 is the first phase III trial of olaparib tablets as maintenance treatment, and it showed a significant benefit in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation,” he said.
The progression-free survival benefit was supported by significant improvements in secondary endpoints with olaparib maintenance. Median time to first subsequent treatment or death was 27.9 months vs. 7.1 months (HR = 0.28; P < .0001). Median progression-free survival after subsequent therapy was not reached in the olaparib arm and was 18.4 months in the control arm (HR = 0.50; P = .0002). Median time to second subsequent therapy or death was also not reached, compared with 18.2 months (HR = 0.37; P < .0001). Overall survival data are currently immature.
“It’s exciting, in that we truly think this is a valid surrogate for overall survival, and the U.S. Food and Drug Administration now accepts progression-free survival as a clinically meaningful endpoint,” Dr. Penson shared. “We anticipate that these findings will change the standard of care and will expand the indication to the second-line treatment of patients with BRCA mutations.”
He further suggested that the seemingly large difference in the findings, according to investigator vs central review, may reflect some “statistical artefact.” Dr. Penson noted: “The curves are not that much different, and the data are not fully mature.” Regardless, he emphasized, the magnitude of the benefit is large. “Instead of disease recurring within 6 months, patients get more than 2 years. That’s substantial.”
Managing Nausea
The treatment was relatively well tolerated, with about 11% of patients discontinuing olaparib due to side effects (vs 2% in the control arm). The chief complaints were nausea, vomiting, and fatigue, which occurred (all grades) in 76%, 37%, and 38%, respectively. Serious adverse events occurred in 18% of the olaparib arm vs 8% of controls, and anemia ≥ grade 3 was observed in 19% and 2%, respectively.
“The new tablet formulation is much more palatable,” Dr. Penson indicated, adding that the tablets, although not formally bioequivalent, maintained at least therapeutic dose levels. However, he added, “it’s a little sobering that 37% of patients vomited at some time during treatment. The trick is to be proactive.”
“Clinicians must warn their patients that they will feel nauseated and could vomit, and they have to have a plan for this,” he recommended. “Patients should leave the office with a prescription for prochlorperazine. By the end of the second week, they may start to have significant nausea. You can hold the tablet for a few days or so and then continue it at the same dose.”
Nausea and vomiting usually abate over time. The study showed no differences in health-related quality of life over the first 12 months, he added.
The remaining question now, according to Dr. Penson, is whether olaparib maintenance might “cure patients” if used as part of front-line therapy. It will also be evaluated for its benefit in patients with a “BRCA-ness” phenotype, caused by a silencing or dysfunction of genes in BRCA1/2-related pathways. This is being retrospectively analyzed in the Study 19 population. ■
Disclosure: Dr. Pujade-Lauraine reported advisory board membership, honoraria, and/or speakers bureau involvement with AstraZeneca and Roche. Dr. Penson reported honoraria; consulting and advisory roles; and receipt of research funding from AstraZeneca, the sponsor of the SOLO2 trial.
References
1. Pujade-Lauraine E, Ledermann JA, Penson RT, et al: Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017.
2. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382-1392, 2012.
