Triplet Maintenance Therapy Effective in Platinum-Sensitive Recurrent Ovarian Cancer

Triplet maintenance therapy with olaparib, pembrolizumab, and bevacizumab led to durable rates of progression-free survival (PFS) and 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. These results were published in Nature Communications.

More specifically, in 44 patients who received the triplet combination, there was a 6-month PFS rate of 88.6% (95% CI, 75.4%-96.2%), successfully achieving the primary objective of the study. The researchers reported that adverse events (AEs) were manageable, and additional investigations revealed promising efficacy outcomes for patients with homologous recombination deficiency (HRD) and those with a PD-L1 combined positive score (CPS) of 1 or higher.

Ovarian cancer is considered platinum sensitive if it recurs at least 6 months after being treated with platinum-based chemotherapy, making it resistant to further platinum-based chemotherapy treatments. Notably, PARP inhibitors like olaparib have proven more beneficial as maintenance therapy in patients with BRCA-mutated ovarian cancer compared with those with wild-type BRCA. Given the limited effectiveness demonstrated by other agents like bevacizumab and pembrolizumab, this trial sought to explore whether the triplet combination could enhance outcomes for individuals with recurrent ovarian cancer and wild-type BRCA genes.

Of the initial 47 patients identified, 3 were deemed ineligible due to thrombocytopenia, hepatitis, and withdrawal of consent, respectively. Eligible patients had received 2 prior rounds of platinum-containing therapy, demonstrated platinum sensitivity after the penultimate regimen, responded to the most recent platinum regimen, maintained that response, and enrolled in the study within 8 weeks after completing the last regimen. Among the 44 enrolled patients, the median age was 61 years, ranging from 43 to 78.

Participants received the following doses until disease progression or intolerable AEs emerged:

• Olaparib 300 mg orally twice daily
• Bevacizumab 15 mg/kg intravenously every 3 weeks
• Pembrolizumab 200 mg every 3 weeks

The administration of pembrolizumab began in the second treatment cycle due to preclinical evidence indicating that combining a PARP inhibitor with an immune checkpoint inhibitor could enhance the immune antitumor activity.

Ovarian cancer | Image Credit: Lars Neumann – stock.adobe.com

Regarding time to progression after penultimate platinum therapy, 12 (27.3%) patients experienced disease progression between 6 and 12 months, 21 (47.7%) between 12 and 24 months, and the other 11 (25%) after 24 months. Additionally, 33 (75%) patients achieved a partial response following their most recent platinum-based therapy, whereas the other 11 achieved a complete response.

At the data cutoff, 23 patients were still undergoing therapy, while 21 patients had discontinued treatment. Of the 21 who stopped, 17 patients experienced disease progression, 2 patients completed 2 years of treatment, 1 patients developed myelodysplastic syndrome (MDS), and 1 patient withdrew consent. The median (IQR) follow-up duration was 22.9 (17.4-24.7) months.

Aside from the successful 6-month PFS rate of 88.6%, the researchers found that 19 patients experienced disease progression, with a median PFS of 22.4 months observed across all patients. Five of these 19 patients saw progression within 6 months, and 1 of the 5 continued treatment beyond 4 months at the clinician's discretion and was still receiving treatment at the data cutoff. Additionally, 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%).

Regarding overall survival, 10 deaths occurred during the trial, with 2 unrelated to the treatment. One patient passed away due to postoperative complications following brain tumor surgery, while another succumbed to complications from subsequent chemotherapy. The median overall survival was 28.6 months (95% CI, 27.3-not reached). The study did not report other secondary end points, such as time to progression, subsequent treatments, time to the second treatment, or progression after next-line treatment, as most patients were still receiving study treatment.

All patients experienced at least 1 AE of any grade, with the most common AEs including 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%. Notably, 23 (52.3%) patients experienced grade 3 or higher AEs, with grade 3 or higher anemia in 22.7%, and 1 patient developed a grade 3 small bowel perforation likely linked to bevacizumab. Another experienced a grade 4 AE in the form of MDS after a year of maintenance, and this patient discontinued treatment but had not experienced disease progression by the data cutoff, making them the only patient to discontinue treatment entirely due to AEs.

In an exploratory analysis, 54.6% of patients were identified as being HRD-positive, with a genomic instability score of at least 42, and 63.6% had a PD-L1 CPS of at least 1. Patients with HRD positivity displayed improved PFS compared with patients who were HRD-negative (P = .043). Likewise, those with a PD-L1 CPS of at least 1 exhibited enhanced PFS compared to those with a PD-L1 CPS less than 1 (P = .001). The analysis revealed no significant difference in PFS based on whether patients achieved a complete or partial response to second-line chemotherapy (P = .5649).

The researchers placed the results in the context of previous combination therapy studies in ovarian cancer. They noted that, compared with single-agent studies, the PFS in this trial appeared more favorable. Another study, MEDIOLA, employed a combination of olaparib, durvalumab, and bevacizumab, but used it as a treatment following platinum-sensitive relapse, not as maintenance therapy after a second-line response.

“Another difference was that the MEDIOLA study screened for patients based on germline BRCA status, whereas our study fully screened for both germline and somatic BRCA,” the researchers noted. “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.”

For a comprehensive understanding of the role of triplet therapy in ovarian cancer, longer-term follow-up on this study, along with more extensive randomized trials, are necessary.

Reference

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. doi:10.1038/s41467-023-40829-2