Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.

Abstract

378 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]

Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities

“…15 However, there was no difference in overall survival, with median overall survival of 19.0 versus 19.2 months (HR, 0.83; 95% CI, 0.56-1.22), although there was a trend toward improved 36-month survival with olaparib (33.9% vs. 17.8%). 16 Olaparib maintenance therapy is now U.S. Food and Drug Administration approved and a standard-of-care option for patients with metastatic pancreatic adenocarcinoma with germline BRCA1/2 mutations after at least 16 weeks of first-line platinum-based chemotherapy.…”

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer

“…The recently published POLO trial reported a significant prolongation of PFS with a PARPi maintenance treatment compared to a placebo [ 14 ]. Although showing a trend for prolonged overall survival (HR 0.83), the follow-up data of the trial could not demonstrate a significant survival benefit in the experimental arm [ 45 ]. This raises the question of whether prolonged PFS is a clinically meaningful endpoint.…”

“…PFS was chosen as the primary endpoint because patients with a g BRCA mutation who have received platinum chemotherapy have prolonged survival and receive multiple subsequent therapies, which could affect OS. The experts emphasised that some patients received PARPi subsequent to the trial [ 14 , 45 ]. The majority of experts (LOA = 90.1%) rated PFS as a clinically meaningful endpoint in patients with BRCA1/2 germline mutations and pancreatic cancer and therefore is a sufficient parameter for clinical use.…”

Recent advances in precision medicine for pancreatic ductal adenocarcinoma

“…A recent phase III trial of olaparib (the POLO trial) displayed considerable improvement in PFS in germline BRCA-mutated metastatic PDAC patients who were sensitive to platinum agents in first-line therapy. 70 In addition, a recent study reported that ATM-mutant PDAC cells were responsive to the olaparib (PARPi) or the ATR inhibitor VE-822, and showed the that treatment with either of these inhibitors induced intense accumulation of DSBs and diminished tumor cell viability in vitro and in vivo. 71 Thus, the subtype of PDAC patients with DDR deficiency is sensitive to platinum analogs and PARP inhibitors.…”