Combination therapy with the PARP inhibitor olaparib and the PD-L1 inhibitor durvalumab induced objective responses in more than 70% of patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.
Yvette Drew, MD
Yvette Drew, MD
Combination therapy with the PARP inhibitor olaparib (Lynparza) and the PD-L1 inhibitor durvalumab (Imfinzi) induced objective responses in more than 70% of patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer, according to results from the phase II MEDIOLA trial.
Overall, 23 of 32 patients had objective responses with olaparib plus durvalumab, including 6 (19%) complete responses. Subgroup analysis showed a consistency of response in patients who had received as many as 3 prior lines of therapy.
“The combination of olaparib and durvalumab was well tolerated, with a low incidence of grade 3 or higher adverse events or all-grade immune-related adverse events,” Yvette Drew, MD, of Newcastle University in Newcastle-Upon-Tyne, England, reported at the 2018 Society of Gynecologic Oncology Annual Meeting.
“Preliminary efficacy results suggest strong activity in relapsed platinum-sensitive ovarian cancer, particularly in early-line patients…Baseline PD-L1 expression and tumor-infiltrating lymphocytes (TILs) did not appear to correlate with clinical outcomes,” added Drew.
Several lines of evidence provide a rationale for evaluating the combination in relapsed, platinum-sensitive ovarian cancer. Olaparib has demonstrated efficacy as maintenance therapy for relapsed platinum-sensitive disease. Recent preclinical studies showed that PARP inhibition upregulates PD-L1, said Drew. Other studies showed that olaparib-induced DNA damage may enhance immune recognition.
Investigators enrolled patients with recurrent platinum-sensitive ovarian cancer with germline BRCA mutations in second-line or later therapy. Eligible patients had no prior exposure to a PARP inhibitor or immune-oncology agent.
Treatment started with a 4-week run-in of olaparib monotherapy and then concurrent treatment with the PARP inhibitor and durvalumab. The primary endpoints were disease control (response plus stable disease) at 12 weeks and safety. Secondary endpoints included disease control at 28 weeks, objective response rate, efficacy by PD-L1 expression, and evaluation of TILs.
The study population had a median age of 58.5, and primary tumor location was in the ovary in 26 of 32 patients. Drew reported that 14 patients had received 1 prior line of therapy and 8 each had received 2 or 3 prior therapies. Additionally, 22 patients had BRCA1 mutations and 10 had BRCA2 mutations, 30 of 32 patients had FIGO stage III or IV disease, and tumors had serous histology in 26 cases.
The safety analysis included 34 patients. The most frequent grade ≥3 adverse event was anemia, occurring in 4 (12%) patients, followed by increased lipase in 3 (9%) patients. No other grade ≥3 toxicity occurred in more than 2 patients. The most common immune-mediated adverse events (all grades) were hypothyroidism in 5 (15%) patients and rash in 4 (12%).
The combination achieved a 12-week disease-control rate of 81%. Drew reported that 6 patients had complete responses and 17 others had partial responses, resulting in an overall response rate of 72%. An additional 3 patients had stable disease, bringing the disease control rate to 81%. Three patients had progressive disease.
Analysis of PD-L1 and TILs in archived tissue showed no statistically significant associations between PD-L1 expression in tumor cells, CD3 or CD8 TILs, and best objective response. Investigators observed a trend toward increased PD-L1 expression and TIL density in patients who had objective responses or stable disease. Additionally, numerically higher PD-L1 expression in tumor cells was observed in patients who had disease control at 12 weeks.
Drew said future evaluation of the combination will include expansion of the BRCA-mutant cohort to a total of 100 patients. Additionally, a patient cohort with relapsed BRCA wild-type tumors will receive the combination. A global phase III trial of the combination as first-line therapy in ovarian cancer is expected to begin by the end of the second quarter of 2018.
Drew Y, de Jonge M, Hong S-H, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC) . Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Late-breaking abstract.