Platinum-Resistant Ovarian Cancer Responds to Combination Therapy That Includes Dostarlimab Plus PARP, VEGF Inhibition

Article

A dostarlimab triplet combination showed promise in a phase 2 study for treatment of patients with platinum-resistant ovarian cancer, according to a presentation at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer.

Antitumor activity as well as tolerability were observed in patients with platinum-resistant ovarian cancer (PROC) treated in the phase 2 OPAL study (NCT03574779), which examined the triplet combination of dostarlimab plus niraparib (Zejula) and bevacizumab (Avastin), according to results presented at the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.1

A total of 41 patients were enrolled in the trial to receive the regimen that included the investigational PD-1 inhibitor. Two patients did not undergo a baseline scan and were excluded from the response-evaluable population (n = 39). Findings from cohort A (NCT02715284) were presented at the SGO meeting.

Antitumor activity was assessed in the response-evaluable population. Patients were eligible if they had high-grade PROC, recurrent epithelial ovarian, fallopian tube, primary peritoneal cancer, or recurrent carcinosarcoma of the ovary. Patients had received 1 to 2 prior lines of anticancer therapy for ovarian cancer, but no prior therapy with anti–PD-1/PD-L1 or PARP inhibitors.

The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1 and secondary end points were progression-free survival (PFS), safety, and disease control rate (DCR). In addition, investigators conducted a post hoc analysis for biomarker genes including BRCA mutation (BRCAm), homologous recombination repair mutation (HRRm), and PD-L1 status using combined positive score (CPS ≥1%).

After undergoing screening for 21 days, patients received 500 mg of intravenous (IV) dostarlimab every 3 weeks for the first 4 doses, then 1000 mg every 6 weeks thereafter, with 15 mg/kg IV bevacizumab every 3 weeks up to 15 months and 300 mg or 200 mg of oral niraparib (determined by baseline weight and platelet count) once daily until discontinuation.

Median patient age was 66 years (range, 37-83) and ECOG performance score was 0 (46.3%) or 1 (53.7%). Eighteen (43.9%) patients had received prior bevacizumab. Biomarker analysis at baseline showed that 9.8% of patients had BRCAm, 82.9% of patients had BRCA wild-type disease (BRCAwt), and 7.3% had unknown BRCA status. HRR analysis revealed that 17.1% of patients had HRRm, 75.6% of patients had HRRwt, and 7.3% had unknown HRR status. The majority of patients (68.3%) had positive PD-L1 status.

“The objective response rate was 17.9% [90% CI, 8.7%-31.1%] with 7 partial responses and zero complete responses,” said lead author Joyce F. Liu, MD, MPH, associate chief and director of clinical research, Division of Gynecologic Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. Response data required that patients with a best response of complete response or partial response undergo a confirmation scan ≥4 weeks after the first scan in which a response was observed.

“Additionally, 23 patients had stable disease as their best response and the overall disease control rate was 76.9% [90% CI, 63.2%-87.4%],” she said. ORR was consistent across most subgroups, but investigators noted that patients who received prior bevacizumab showed a lower, nonsignificant, response rate (6%).

When reviewing best percentage change from baseline by HRR and PD-L1 status, the investigators noted that no correlation between these biomarkers or activity was observed. Median PFS in the total population (n = 41) was 7.6 months (95% CI, 4.2-10.6).

Comparatively, a prior phase 1/2 trial (NCT02657889) evaluating niraparib and pembrolizumab (Keytruda) showed an ORR of 18% in patients with PROC or who were otherwise ineligible for further platinum-based therapies.2

Overall the safety profile for patients in cohort A was consistent with the prior experience for each individual drug, and 97.6% of patients reported at least 1 any-grade treatment-related adverse effect (TRAE). Specifically, the most common total reported any-grade TRAEs that occurred with an overall incidence of ≥10% were fatigue (61.0%), thrombocytopenia event (48.8%), and hypertension (43.9%). The most common grade 3 TRAEs with an incidence ≥5% were hypertension (22.0%) and thrombocytopenia event (22.0%).

No TRAEs resulted in death and 34.1% of patients discontinued at least 1 of the 3 study drugs because of a TRAE.

“Although multiple patients [14.6%] developed grade 3 or higher small bowel obstructions, all were assessed as not being related to study drug,” said Liu, who is also assistant professor of medicine at Harvard Medical School. “One patient did develop a grade 4 bowel perforation event that was assessed as related to bevacizumab,” she said.

Liu noted that the majority of patients enrolled had BRCAwt or HRRwt tumors, and that 43.9% of patients had platinum-resistant disease, both of which are predictive factors associated with lower responses to therapy. However, “there were no clear response trends based on biomarkers,” she said.

References

1. Liu JF, Gaillard S, Wahner Hendrickson AE, et al. An open-label phase II study of dostarlimab (TSR-042), bevacizumab (bev), and niraparib combination in patients (pts) with platinum-resistant ovarian cancer (PROC): Cohort A of the OPAL trial. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women's Cancer; March 19-25, 2021; Virtual Abstract 23.

2. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5(8):1141-1149. doi:10.1001/jamaoncol.2019.1048

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