In Relapsed Ovarian Cancer, Responses Achieved With PARP/Checkpoint Inhibitor Combo

Yvette Drew, MD

According to results from the phase II MEDIOLA trial, the combination of olaparib (Lynparza), a PARP inhibitor, and durvalumab (Imfinzi), a PD-L1 inhibitor, was found to induce objective responses in over 70% of patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.

In this trial, 23 of 32 patients had objective responses with the combination regimen of olaparib plus durvalumab. This included 6 (19%) complete responses and a subgroup analysis which 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."

For patients with relapsed, platinum-sensitive ovarian cancer, multiple lines of evidence have provided rationale for evaluating treatment with this combination. Olaparib has shown efficacy as a maintenance therapy for relapsed platinum-sensitive disease. Preclinical studies showed that PARP inhibition upregulates PD-L1, said Drew. Other studies demonstrated that olaparib-induced DNA damage could strenghten the immune recognition.

Patients with recurrent platinum-sensitive ovarian cancer and germline BRCA mutations in second-line or later therapy were enrolled in the trial. To be considered eligible, patients had to have had no prior exposure to a PARP inhibitor or immune-oncology agent.

Treatment started with a 4-week run-in of olaparib monotherapy followed by 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.

Safety analysis looked at 34 patients. The most frequent grade ≥3 adverse event (AE) was anemia, which was found in 4 (12%) patients, followed by increased lipase in 3 (9%) patients. No other grade ≥3 AEs occurred in more than 2 patients. The most common immune-mediated AEs (all grades) were hypothyroidism in 5 (15%) patients and rash in 4 (12%).

This treatment demonstrated a 12-week disease-control rate of 81%. Drew also shared results concluding 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%. Also, 3 patients had progressive disease.

The analysis of PD-L1 and TILs in archived tissue demonstrated no statistically significant associations between PD-L1 expression in tumor cells, CD3 or CD8 TILs, and best objective response. A trend toward increased PD-L1 expression and TIL density in patients who had objective responses or stable disease, however, was observed. Numerically higher PD-L1 expression in tumor cells was found in patients who had disease control at 12 weeks.

Drew said future evaluation will include expansion of the BRCA-mutant cohort to a total of 100 patients to strengthen results. A patient cohort with relapsed BRCA wild-type tumors will receive the combination as well. A global phase III trial is expected to begin by the end of second quarter of 2018, looking at this particular combination as first-line therapy for patients with ovarian cancer.

Reference:

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.