Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study

Abstract

Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts).

Patients and methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts).

Results: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1-97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5-43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2-86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia.

Conclusions: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

Figure 1.

MEDIOLA second-stage ovarian cancer cohorts: study design. *In the non-gBRCAm cohorts, patients were enrolled into the triplet and doublet cohorts sequentially following confirmation of non-gBRCAm status; patients were enrolled into the doublet cohort once enrollment into the triplet cohort was complete. The gBRCAm expansion doublet cohort was enrolled concurrently alongside the non-gBRCAm cohorts; ^†All tumor assessment-related endpoints were based on investigator-assessed radiologic response (RECIST 1.1). BID, twice daily; gBRCAm, germline BRCA1 and/or BRCA2 mutation; IO, immuno-oncology; IV, intravenous; PBC, platinum-based chemotherapy; po, by mouth; q2w, every 2 weeks; q4w, every 4 weeks.

Figure 2.

Percentage change from baseline in target tumor size in the (A) gBRCAm expansion doublet cohort, (B) non-gBRCAm doublet cohort and (C) non-gBRCAm triplet cohort, (D) ORR by GIS in non-gBRCAm doublet and triplet cohorts and (E) ORR by PD-L1 status in the gBRCAm expansion doublet cohort and non-gBRCAm doublet and triplet cohorts. Best change in target lesion size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. The best change is displayed for each patient, by descending percentage change. Dashed reference lines at −30% and 20% indicate RECIST thresholds for partial response and progressive disease, respectively. Values greater than 100% or less than −100% are displayed as 100% and −100%, respectively. *Determined by Foundation Medicine Inc. (Cambridge, MA) tumor analysis: GIS-positive is defined as genome-wide LOH ≥ 14, sBRCAm, or a mutation in ATM, BRIP1, PALB2, RAD51C, BARD1, CDK12, CHEK1, CHEK2, FANCL, PPP2R2A, RAD51B, RAD51D, or RAD54L. At the time of analysis, the cutoff for genome-wide LOH was 14% (35). GIS-negative is defined as genome-wide LOH < 14, no sBRCAm and no mutation in ATM, BRIP1, PALB2, RAD51C, BARD1, CDK12, CHEK1, CHEK2, FANCL, PPP2R2A, RAD51B, RAD51D, or RAD54L. GIS-unknown status is due to sample not being analyzable (i.e., poor quality, technical failure, or inadequate tissue). ^†Percentages for ORR are based on the number of patients in that tumor cell or immune cell expression category. BRCAm, BRCA1 and/or BRCA2 mutation; gBRCAm, germline BRCAm; GIS, genomic instability status; sBRCAm, somatic BRCAm; SD, standard deviation.

Figure 3.

Kaplan–Meier estimates of PFS in the (A) gBRCAm expansion doublet cohort, (B) non-gBRCAm doublet cohort and (C) non-gBRCAm triplet cohort, and OS in the (D) gBRCAm expansion doublet cohort, (E) non-gBRCAm doublet cohort and (F) non-gBRCAm triplet cohort. Dashed lines represent 95% CIs. A–C, Progression events that occurred after two or more missed visits, or within two visits of baseline where the patient had no evaluable visits or did not have a baseline assessment, were censored. D–F, Patients who had not died were censored at their last known alive date. gBRCAm, germline BRCA1 and/or BRCA2 mutation; NC, not calculable.