Clinical and molecular characteristics of patients with short- and long-term progression-free survival in the phase IIIb OPINION study of maintenance olaparib for patients with non-germline BRCA1/BRCA2-mutated platinum-sensitive relapsed ovarian cancer (306)

Abstract

<b>Objectives:</b> The OPINION study (NCT03402841) demonstrated the activity of maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) without a germline <i>BRCA1</i>/<i>BRCA2</i> mutation (non-g<i>BRCA</i>m), with an overall median progression-free survival (PFS) of 9.2 months (mo) (Poveda <i>et al</i>. ASCO 2021). We further explored clinical and molecular characteristics in pts with long-term (LT) and short-term (ST) PFS. <b>Methods:</b> Pts with non-g<i>BRCA</i>m PSR OC and ≥2 prior lines of platinum-based chemotherapy (PBC) incomplete/partial response (CR/PR) to their last PBC received maintenance olaparib (300 mg bid) until progression/unacceptable toxicity. Here, pts were grouped by time from the first dose until disease progression (RECIST v1.1) or death: >18 mo for the LT group and <4 mo for the ST group (chosen based on radiologic scan timings and follow up). Pts who discontinued the study >18 mo after the first dose were also in the LT group. Samples were analyzed using the Myriad myChoice HRD plus and BRACAnalysis CDx assays. Molecular analyses included: tumor <i>BRCA</i>m (t<i>BRCA</i>m); somatic <i>BRCA</i>m (s<i>BRCA</i>m), defined as the presence of a t<i>BRCA</i>m and no g<i>BRCA</i>m; homologous recombination deficiency (HRD), defined as a genomic instability score ≥42 and/or t<i>BRCA</i>m; homologous recombination repair (HRR) gene mutations, excluding <i>BRCA</i>m (non<i>-BRCA</i> HRRm), based on a prespecified 13-gene panel; and <i>TP53</i> mutation status. <b>Results:</b> Of 279 pts in OPINION, 67 (24%) and 65 (23%) had LT and ST PFS, respectively. At diagnosis, 45/67 pts (67%) in the LT group had FIGO stage III and 15 (22%) had stage IV disease; 47/65 (72%) in the ST group had stage III and 12 (18%) had stage IV disease. Median (range) prior PBC regimens was 2 (2-5) and 2 (2-6) in the LT and ST groups, respectively. About 34/67 (51%) and 12/65 (18%) pts achieved CR to their last PBC, and 33/67 (49%) and 52/65 (80%) had PR in the LT and ST groups, respectively; 48/67 (72%) and 42/65 (65%) had a platinum-free interval of ≥12 mo in the LT and ST groups, respectively. Fifteen out of 67 (22%) and 5/65 pts (8%) were found to have a t<i>BRCA</i>m in the LT and ST groups, respectively; 47/67 (70%) and 25/65 pts (40%) had HRD-positive tumors. Fifteen (22%) and 5 (8%) pts had a non-<i>BRCA</i> HRRm in the LT and ST groups, respectively, although 65% of pts with a non-<i>BRCA</i> HRRm had HRD-positive tumors. Twenty-five (37%) and 32 (49%) had <i>TP53</i>-disruptive mutations in the LT and ST groups, respectively. Overlap between t<i>BRCA</i>m, HRD, non-<i>BRCA</i> HRRm (including most frequently mutated genes), and <i>TP53</i> mutations is shown in the Figure. <b>Conclusions:</b> Pts with LT PFS (>18 mo) in OPINION more commonly had HRD-positive tumors, with or without a t<i>BRCA</i>m, than pts with ST PFS (<4 mo), consistent with results showing longer PFS among pts with HRD-positive tumors in the overall population. A higher proportion of pts with LT than ST PFS achieved CR to their last PBC. However, pts could achieve LT PFS regardless of clinical and molecular factors, reinforcing the benefit of maintenance PARP inhibition in non-g<i>BRCA</i>m PSR OC.