Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
Authors: Golan Talia , Hammel Pascal , Reni Michele , Van Cutsem Eric , Macarulla Teresa , Hall Michael J. , Park Joon Oh , Hochhauser Daniel , Arnold Dirk , Oh Do-Youn , Reinacher-Schick Anke C. , Tortora Giampaolo , Algül Hana , O'Reilly Eileen Mary , McGuinness David , Cui Karen , Schlienger Katia , Locker Gershon Y. , Kindler Hedy L. 
Published: January 2021

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Background: POLO is the first phase 3 trial to evaluate maintenance therapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib (O) in patients with metastatic pancreatic cancer (mPaC) and a germline BRCA mutation ( gBRCAm) whose disease had not progressed on first-line platinum-based chemotherapy (PBC). POLO demonstrated that patients had significantly longer progression-free survival (PFS; primary endpoint) with maintenance O than with placebo (P; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.35–0.82; p= 0.004). Herein, we present final overall survival (OS) data. Methods: POLO was a randomized, double-blind, placebo-controlled trial (NCT02184195) conducted at 119 sites in 12 countries. Eligible patients had mPaC without disease progression for ≥16 weeks on PBC and a deleterious or suspected deleterious gBRCAm. Patients were randomized 3:2 to O (300 mg tablet twice daily) or P. OS (time from randomization until death) was a key secondary endpoint assessed using a log-rank test. A multiple-testing procedure (MTP) was used, with alpha passed to OS owing to a significant PFS result. Time from randomization to second disease progression or death (PFS2), to discontinuation of treatment (TDT), and to initiation of first (TFST) or second (TSST) subsequent therapies following treatment discontinuation or death were secondary endpoints (log-rank test, not in MTP). Primary analysis of OS after 108 deaths; data cut-off (DCO) July 21 2020. Results: Ninety-two and 62 patients were randomized to O and P, respectively; those censored had a median follow-up of 31.3 months (mo) and 23.9 mo, respectively. At DCO, n = 13 remained on O; n = 2 on P. OS was similar for the O and P groups (median 19.0 and 19.2 mo, respectively; HR 0.83 favoring O; 95% CI 0.56–1.22; p= 0.3487). OS at 36 mo was 33.9% for O and 17.8% for P. Median PFS2 was 16.9 mo for O vs 9.3 mo for P (HR, 0.66; 95% CI 0.43–1.02; p= 0.0613). TFST, TSST and TDT were longer with O than P (Table). TDT at 24 mo was 24.3% for O vs 3.3% for P; at 36 mo was 17.2% for O vs 3.3% for P. Incidence of grade ≥3 adverse events (AEs) was 49% for O (anemia most common [12.2%]); 25% for P (anemia, hyperglycemia, upper abdominal pain most common [3.3%]). Treatment was discontinued owing to AEs for 8.9% patients in the O arm vs 1.6% for P. Conclusions: Although HR for OS was in favor of maintenance O vs P among patients with a gBRCAm and mPaC whose disease had not progressed during PBC, there was no statistically significant difference. PFS2 showed a clear trend for treatment benefit beyond disease progression in favor of O, but was not alpha protected. Safety data were consistent with the primary analysis. Clinical trial information: NCT02184195. [Table: see text]