According to recently announced topline findings, the confirmatory phase III SOLO-3 trial of olaparib has met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in objective response rate in patients with <em>BRCA</em>-mutant ovarian cancer who have relapsed on at least 2 prior lines of therapy
Sean Bohen, MD, PhD
According to recently announced topline findings, the confirmatory phase III SOLO-3 trial of olaparib (Lynparza) has met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in objective response rate (ORR) in patients withBRCA-mutant ovarian cancer who have relapsed on at least 2 prior lines of therapy.1
SOLO-3 also met the key secondary endpoint of significantly improved progression-free survival (PFS) compared with chemotherapy. Additionally, the safety profile and tolerability of olaparib was consistent with prior studies.
“We are very excited about SOLO-3, which is the first phase III trial for a PARP inhibitor to demonstrate a positive result versus chemotherapy in advanced ovarian cancer where effective options are needed,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer, AstraZeneca, said in a press release. “We look forward to sharing the full results at a forthcoming medical meeting.”
SOLO-3 was conducted as a postapproval commitment in agreement with the FDA. AstraZeneca and Merck, the co-developers of olaparib, will discuss these results with the agency.
The multicenter, open-label, controlled, SOLO-3 trial enrolled 266 patients with relapsed ovarian cancer with deleterious or suspected deleteriousBRCA1/2mutations who received 2 or more prior lines of therapy. Patients were randomized 2:1 to receive 300 mg of olaparib tablets twice daily or physician’s choice of single-agent chemotherapy of paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine. The primary endpoint was ORR by blinded independent central review and key secondary endpoints included PFS, time to second disease progression or death, and overall survival.
To be eligible for enrollment, patients must be ≥18 years of age; have histologically diagnosed relapsed high grade serous ovarian cancer, including primary peritoneal and/or fallopian tube cancer, or high-grade endometroid cancer; germlineBRCAmutations; ≥1 lesion that can be accurately assessed at baseline; must have received ≥2 prior platinum-based lines of chemotherapy; normal organ and bone marrow function; and an ECOG performance status between 0 and 2.
Patients withBRCA1/2mutations that are considered to be non-detrimental, have exposure to any investigational product within 30 days, prior PARP inhibitor treatment, those with platinum-resistant/refractory disease, received systemic chemotherapy within 3 weeks prior to first dose of study treatment, or prior single-agent treatment to one of the above selected chemotherapy regimens were excluded.
Olaparib was initially granted an accelerated approval in December 2014 for the treatment of patients withBRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy. Along with the drug, the FDA also approved a molecular companion diagnostic test, BRACAnalysis CDx®, developed by Myriad Genetics, Inc, to detect the presence ofBRCAmutations in blood samples. Accelerated approvals are contingent on the results of confirmatory trials.
The accelerated approval for olaparib was based on a 34% ORR seen in 137 patients withBRCA-positive ovarian cancer who had received at least 3 lines of chemotherapy in a single-arm phase II trial, known as Study 42.2
In this study, eligible patients were treated with oral olaparib capsules at 400 mg twice daily until disease progression, according to RECIST v1.1 criteria. ORR and duration of response (DoR) were assessed for patients with measurable disease at baseline.
Updated findings showed that in patients with germlineBRCA1/2-mutant ovarian cancer, the ORR was 34% (95% CI, 26%-42%) and the median DoR was 7.9 months (95% CI, 5.6-9.6).3In platinum-resistant tumors, the ORR in platinum-resistant tumors was 30%. Additionally, the median DoR for platinum-sensitive and platinum-resistant disease was similar at 8.2 months (95% CI, 5.6-13.5) versus 8.0 months (4.8-14.8), respectively.
In December 2018, the FDA approved olaparib as a maintenance treatment for patients with deleterious or suspected deleterious germline or somaticBRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.
The agency also approved BRACAnalysis CDx®to be used by healthcare professionals to identify patients with advanced ovarian cancer who have a germlineBRCAmutation and are eligible for first-line maintenance therapy with olaparib in this setting.
Olaparib also has a third indication in ovarian cancer. In August 2017, the FDA approved olaparib tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless ofBRCAstatus.