Triplet Maintenance Shows Efficacy in Platinum-Sensitive Recurrent Ovarian Cancer

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Maintenance therapy with olaparib (Lynparza), pembrolizumab (Keytruda), and bevacizumab (Avastin) led to durable rates of progression-free survival (PFS), as well as tolerability in patients with BRCA1/2 wild-type platinum-sensitive recurrent ovarian cancer, according to results from the multicenter, single-arm, phase 2 OPEB-01/APGOT-OV4 study (NCT04361370) published in Nature Communications.¹

In 44 patients who received the triplet combination, there was a 6-month PFS rate of 88.6% (95% CI, 75.4-96.2), meeting the study’s primary end point. Adverse events (AEs) were manageable, according to investigators. Additionally, exploratory analyses showed favorable efficacy for those with homologous recombination deficiency (HRD), as well as those with PD-L1 combined positive score (CPS) of 1 or greater.

Patients with ovarian cancer who recur after a treatment-free interval of at least 6 months after platinum-based chemotherapy are considered platinum-sensitive and have resistance to additional platinum-based chemotherapy. PARP inhibitors, such as olaparib, showed greater benefit as maintenance therapy in patients with BRCA-mutated ovarian cancer than those with wild-type BRCA.

Based on other studies that have shown limited efficacy with agents besides PARP inhibitors, including bevacizumab and pembrolizumab, this trial sponsored by Yonsei University in Seoul, South Korea, was designed to investigate whether the triplet combination would improve outcomes in patients with recurrent BRCA gene wild-type ovarian cancer.

Patients received olaparib 300 mg orally twice daily, bevacizumab at 15 mg/kg every 3 weeks intravenously, and 200 mg of pembrolizumab every 3 weeks until progression or unacceptable toxicity. Pembrolizumab was initiated in cycle 2 based on preclinical evidence that PARP inhibition’s immune antitumor activity would be enhanced with the combination of an immune checkpoint inhibitor.

Forty-seven patients were identified; 3 were ineligible because of thrombocytopenia, hepatitis, and consent withdrawal, respectively. Patients had to have received 2 prior courses of platinum-containing therapy, be platinum-sensitive to the next-to-last regimen, responded to the last platinum regimen, remain in response, and be enrolled in the study within 8 weeks of completion of the last regimen.

Of the 44 patients who were enrolled between October 20, 2020, and March 22, 2022, the median age was 61 (range, 43-78). Twelve (27.3%) patients progressed between 6 and 12 months after their next-to-last platinum therapy, and 33 (75%) patients had a partial response after their most recent platinum-based therapy, with the rest having a complete response. One had received a prior PARP inhibitor and 9 had already received bevacizumab as primary maintenance therapy.

At the data cut-off, 23 patients were still receiving therapy. Twenty-one discontinued therapy, 17 of whom had progressive disease, 2 who completed 2 years of treatment, 1 who had myelodysplastic syndrome (MDS), and 1 who withdrew consent. The median duration of follow-up was 22.9 months (interquartile range, 17.4-24.7).

Nineteen patients showed disease progression after a median of 13.7 months (interquartile range, 8.6-20.8). The median PFS for all patients was 22.4 months (20.4-not reached). The 12-month PFS rate was 84.0% (95% CI, 69.3%-92.0%), and the 18-month PFS rate was 71.4% (95% CI, 54.9%-82.7%).

In terms of overall survival, there were 10 deaths on the trial, including 2 unrelated to treatment. One death was due to post-operative complications from surgery for a primary brain tumor, and the other was due to complications from subsequent chemotherapy. Median OS was 28.6 months (95% CI, 27.3-not reached). Other secondary end points included time to progression, subsequent treatment, time to second treatment, and progression after next-line treatment, and were not reported as most patients were still receiving study treatment.

Five of the 19 patients whose disease progressed did so within 6 months. One of these patients who progressed after 4 months continued treatment at clinician’s discretion and was still receiving treatment at data cutoff.

All patients reported at least 1 AE of any grade, with the most common AEs being nausea in 59.1% of patients, dyspepsia in 56.8%, proteinuria in 43.2%, general weakness in 40.9%, anemia in 38.6%, and neutropenia in 38.6%. There were grade 3 or higher AEs in 23 patients (52.3%), with grade 3 or higher anemia in 22.7%. One patient developed a grade 3 small bowel perforation that was determined to probably be related to bevacizumab, and another developed MDS, a grade 4 AE, after 1 year of maintenance. The patient with MDS discontinued treatment but had not progressed as of data cutoff. This was the only patient to discontinue treatment fully due to AEs.

Twenty-seven patients (61.4%) required a dose reduction of olaparib. Dose interruptions were required in 38 patients (86.4%) for any of the study drugs: 32 (72.7%) for olaparib, 34 (77.3%) for pembrolizumab, and 33 (75.0%) for bevacizumab. Four patients discontinued bevacizumab and continued receiving the other 2 drugs.

Immune-mediated AEs were reported in 36 patients (81.8%), and 7 (15.9%) experienced grade 3 immune-related AEs. No grade 4 immune-mediated AEs were observed.

The exploratory analysis of biomarkers investigated the 54.6% who were HRD-positive (genomic instability score ≥ 42), and the 63.6% who had PD-L1 CPS of at least 1. HRD-positive patients had an improved PFS vs HRD-negative patients (P =.043). Those with PD-L1 CPS ≥ 1 had improved PFS vs those with PD-L1 CPS < 1 (P =.001). There was no significant difference in PFS depending on patients who had complete response vs partial response to second-line chemotherapy (P =.5649).

The investigators discussed the study’s results in the context of other studies of combination therapies in ovarian cancer. In comparison with single-agent studies, the PFS in this study appeared more favorable. The MEDIOLA study (NCT02734004) used the combination of olaparib, durvalumab (Imfinzi), and bevacizumab, but as a treatment following platinum-sensitive relapse rather than as maintenance following a second-line response, and only screened patients for germline, not somatic, BRCA alterations. The phase 3 DUO-O trial (NCT03737643) investigated triplet maintenance with olaparib, durvalumab, and bevacizumab in BRCA­–wild-type patients, but this was following first-line chemotherapy plus durvalumab and bevacizumab.

Longer-term follow-up on this study as well as additional larger randomized studies are needed to understand the role of triplet therapy in ovarian cancer.

“In this study that exclusively included BRCA wild-type patients with platinum-sensitive recurrent ovarian cancer, the median PFS was 22.4 months. However, further maturation of the PFS data is necessary to elucidate the magnitude of benefit in maintenance versus treatment setting,” the investigators stated.

^Reference:

^{1. Kim YN, Park B, Kim JW, et al. Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4. Nat Commun. 2023;14(1):5476. Published 2023 Sep 6. doi:10.1038/s41467-023-40829-2}