Combination Therapy May Improve Outcomes for Patients with Ovarian Cancer

Advanced ovarian cancer refers to cancer that has spread outside of the ovary. In most cases, the cancer has spread to distant sites, such as the liver or the lungs.

The standard of care for patients with advanced ovarian cancer is debulking surgery and platinum-taxane chemotherapy. Although most patients respond to these treatments, nearly all patients will eventually develop resistance to platinum-based chemotherapy and relapse. Therefore, identifying effective therapies that can overcome platinum resistance has the potential to improve clinical outcomes.

The first FDA-approved combination therapy for ovarian cancer was bevacizumab (Avastin; Genentech) plus chemotherapy, which is used as first-line and maintenance therapy for patients with newly diagnosed disease. The approval of this combination in 2018 was based on results from the Gynecologic Oncology Group protocol 0218, a phase 3, randomized, placebo-controlled, double-blind, multinational clinical trial that met its primary end point of improved progression-free survival (PFS).

Potential synergistic interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and other cell-signaling pathway inhibitors are being evaluated. Results of a phase 2 trial showed that combining the antiangiogenic agent cediranib with the PARP inhibitor olaparib (Lynparza; AstraZeneca) improved PFS compared with olaparib alone (17.7 months vs 9.0 months; P = .005) in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Subgroup analysis showed increased activity of this combination regimen in patients with wild-type or unknown BRCA mutation status, which the investigators postulated may be attributed to greater synergy of the combination in the setting of hypoxia.

Combining PARP inhibitors with immune checkpoint inhibitors has also been explored in the treatment of patients with ovarian cancer with promising results. Results from 2 trials (TOPACIO and MEDIOLA) are showing the potential benefit of such combinations.

In the phase 1/2 TOPACIO trial, patients with heavily pretreated platinum-resistant or secondarily platinum-refractory ovarian cancer were treated with niraparib (Zejula; GlaxoSmithKline) plus pembrolizumab (Keytruda; Merck). In the 60 evaluable patients who received the recommended phase 2 dosing of niraparib 200 mg orally once daily and pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle, the overall response rate (ORR) was 25% and the disease control rate was 68%. In the 11 evaluable patients with BRCA1/2 mutations, the ORR was 45% and the disease control rate was 73%.

In the phase 1/2 MEDIOLA trial, patients with select advanced solid tumors were treated with olaparib plus durvalumab (Imfinzi; AstraZeneca). Eligible patients had no prior exposure to a PARP inhibitor or immuno-oncology agent. In the phase 2 portion of the trial, which included patients with platinum-sensitive ovarian cancer and germline BRCA1/2 mutations, the ORR was 71.9% and the disease control rate was 65.6% at 28 weeks. Median PFS was 11.1 months, with a median duration of response of 10.2 months. Median overall survival was not reached, and 87.0% of patients were alive at 24 months.

Studies are underway to determine the benefits of PARP inhibitor monotherapy versus combination therapy in ovarian cancer and to identify optimal treatment algorithms in various settings (eg, first-line, second-line, maintenance).

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