Olaparib Rechallenge Improves PFS in Relapsed Ovarian Cancer Previously Treated With PARP Inhibition

Rechallenge with maintenance olaparib (Lynparza) following response to platinum-based chemotherapy significantly improved progression-free survival (PFS) in heavily pretreated patients with relapsed ovarian cancer, irrespective of BRCA status, according to results of the phase 3 OReO/ENGOT Ov-38 (NCT03106987) study that were presented during the 2021 ESMO Congress.¹

Data showed that the median PFS improved from 2.8 months in patients who received placebo to 4.3 months in those randomized to rechallenge with olaparib among the cohort of patients with BRCA-mutant ovarian cancer (HR, 0.57; 95% CI, 0.37-0.87; P = .022). In the non–BRCA-mutant cohort, the median PFS improved similarly with olaparib rechallenge from 2.8 months in the placebo arm to 5.3 months in the olaparib arm (HR, 0.43; 95% CI, 0.26-0.71; P = .0023).

The data are the first to demonstrate a benefit to PARP inhibitor rechallenge in patients with platinum-sensitive relapsed ovarian cancer, said Eric Pujade-Lauraine, MD, PhD, of ARCAGY-GINECO in Paris, France, in a virtual presentation during the meeting.

“In both BRCA-mutant and non–BRCA-mutant cohorts, a proportion of patients derived clinically relevant long-term benefit from maintenance olaparib rechallenge,” he said.

Although most patients with newly diagnosed or platinum-sensitive relapsed ovarian cancer achieve long-term responses to PARP inhibitors as maintenance therapy, the majority of them will relapse. It has been unknown whether patients who relapse on PARP inhibition will have a benefit from rechallenged PARP inhibitor therapy following responde to platinum-based chemotherapy.

OReO/ENGOT Ov-38 is a phase 3, randomized, double-blind trial that enrolled 220 patients with nonmucinous platinum-sensitive relapsed ovarian cancer who received 1 prior line of PARP inhibitor maintenance and were in response to their most recent platinum-based chemotherapy. Two cohorts were enrolled, a BRCA-mutant cohort (n = 112) and a non–BRCA-mutant cohort (n = 108), both of which were randomized 2:1 to olaparib at 300 mg (or 250 mg if 300 mg was not previously tolerated) or placebo until progression.

Eligible patients must have had a complete response (CR) or partial response to their most recent platinum regimen or no evidence of disease after surgery without a rise in their CA-125 level. The BRCA-mutant cohort must have had prior PARP inhibitor exposure for at least 18 months after first-line chemotherapy, or at least 12 months after second-line or later chemotherapy. For the non–BRCA-mutant cohort, prior PARP inhibitor exposure for at least 12 months after frontline chemotherapy or at least 6 months after second- or later-line chemotherapy was required.

Patients were stratified by prior bevacizumab (Avastin) and 3 or fewer or at least 4 prior lines of platinum-based chemotherapy. The primary end point was investigator-assessed PFS; secondary end points were time to RECIST/CA-125 progression or death, time to first and second subsequent therapy or death, time to treatment discontinuation or death, overall survival, health-related quality of life, and safety.

In the BRCA-mutant cohort, the median age was 58.5 years (range, 37-80) in the olaparib arm and 61.5 years (range, 44-87) in the placebo arm. Forty-two percent of patients in each arm had 3 prior lines of any chemotherapy, and 23% and 21% in the olaparib and placebo arms, respectively, had exposure to more than 4 prior lines. Thirty-five percent of the olaparib arm and 42% of the placebo arm had exposure to more than 4 prior lines of platinum-based chemotherapy. The best response to platinum-based chemotherapy prior to study entry was a CR in 20% and 34% of the olaparib and placebo arms, respectively.

In the non–BRCA-mutant cohort, the median age was 66.5 years (range, 29-81) in the olaparib arm and 62.5 years (range, 43-77) in the placebo arm. Twenty-eight percent and 22%, respectively, had more than 4 lines of any prior chemotherapy, and 32% and 31%, respectively, had at least 4 prior lines of platinum-based chemotherapy. Best response to platinum-based chemotherapy prior to study entry was a CR in 26% of the olaparib group and 31% of the placebo group.

The median duration range of prior PARP inhibitor therapy was 18.3 to 21.2 months in the BRCA-mutant cohort and 12.4 to 12.6 months in the non–BRCA-mutant cohort. Sixty-one percent of the BRCA-mutant cohort had a duration of prior PARP inhibitor exposure of at least 18 months, and 53% to 57% of the non–BRCA-mutant cohort had a duration of prior PARP inhibitor exposure of at least 12 months.

Prior PARP inhibitors given in the BRCA-mutant and non–BRCA-mutant cohort was olaparib (93% vs 21%, respectively), niraparib (Zejula; 4% vs 64%), rucaparib (Rubraca; 1% vs 10%), veliparib (0% vs 4%), blinded therapy (0% vs 4%), and placebo (3% vs 0%).

Homologous recombination deficiency (HRD) status was positive in about 40% of the non–BRCA-mutant cohort, with HRD status unknown in up to one quarter of patients in this cohort.

In the BRCA-mutant cohort, treatment is ongoing in 9% of patients on the olaparib arm and 3% of the placebo arm; in the non–BRCA-mutant cohort, these percentages are 29% and 17%, respectively. About 60% of patients on the BRCA-mutant cohort discontinued the study, 90% of which were due to death. Twenty-eight percent of those in the non–BRCA-mutant cohort discontinued, with 67% (olaparib arm) and 73% (placebo arm) discontinuing due to death.

“A proportion of patients derived long-term benefit in the olaparib arm,” said Pujade-Lauraine, as the PFS rates in the BRCA-mutant cohort at 12 months after randomization were 19% in the olaparib arm vs 0% in the placebo arm.

In the non–BRCA-mutant cohort, “long-term benefit was again observed—14% of patients in the olaparib arm being free of disease progression [at 12 months] vs 0% in the placebo arm,” he added. In exploratory analyses, the benefit of olaparib in the non–BRCA-mutant cohort appeared consistent, irrespective of HRD status.

In both cohorts, the PFS benefit to olaparib was observed across subgroups, and was irrespective of HRD status. No new safety signals were observed and the rate of discontinuations due to adverse events was low, said Pujade-Lauraine.

Clare L. Scott, MBBS, PhD, chair of Gynecological Cancer at University of Melbourne, Australia, who served as a discussant on the abstract, said that the results from OReO/ENGOT Ov-38 provide some rules to identify patients who would benefit based on prior PARP inhibitor exposure.

“All clinical groups appear to benefit except for patients who had a short time on treatment prior to coming on to study, but really we need to define the molecular groups who benefit from alternative therapies or combination PARP inhibitor therapies,” Scott said.

Reference

1. Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): phase IIIb OReO/ENGOT Ov-38 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA33.