Combo of Alpelisib and Olaparib Falls Short in Ovarian Cancer

The combination of the PI3K inhibitor alpelisib (Piqray) and the PARP inhibitor olaparib (Lynparza) did not improve progression-free survival (PFS) in patients with platinum-resistant/refractory, BRCA wild-type high-grade serous ovarian cancer (HGSOC), missing the primary end point of the phase 3 EPIK-O/ENGOT-OV61 trial.¹

At a median follow-up of 9.3 months, the median PFS per blinded independent review was 3.6 months with the combination vs 3.9 months with chemotherapy (HR, 1.14; 95% CI, 0.88–1.48; P =.84). The median overall survival (OS) was 10.0 months versus 10.6 months, respectively (HR, 1.22; 95% CI, 0.87–1.71). The objective response rate (ORR) was 15.6% with alpelisib (Piqray) plus olaparib compared with 13.5% with chemotherapy.

No new safety signals emerged in the trial compared with previous research with the drugs as individual agents.

“In this analysis of the EPIK-O/ENGOT-ov61 trial, the primary end point was not met; the combination of alpelisib and olaparib did not have a PFS benefit compared with single-agent chemotherapy of physician’s choice in patients with platinum-resistant/platinum-refractory HGSOC with no BRCA mutation,” lead study author Panagiotis A. Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors wrote in their article, which was published in the Journal of Clinical Oncology (JCO).

Patient Characteristics and Study Design

The open-label phase 3 EPIK-O/ENGOT-OV61 trial enrolled 358 patients with platinum-resistant/refractory HGSOC that did not harbor germline or somatic BRCA mutations. Patients had received at least 1 prior therapy. Unless contraindicated, prior bevacizumab (Avastin) was required, and patients were allowed to have received prior PARP inhibitor treatment.²

Across both treatment arms, the median age was 61 years (range, 32–84) and about two-thirds of patients were aged younger than 65 years. The ECOG performance status was 0 in about two-thirds of patients and 1 in about one-third of patients. Ascites were present in 21.7% of the alpelisib plus olaparib group and 16.9% of the chemotherapy group. Serous adenocarcinoma was the predominant histology at 92.2% vs 97.2% in the combination and chemotherapy arms, respectively.¹

The number of metastatic sites included1 (40.6% vs 44.4% in the treatment vs control arms, respectively), 2 (38.9% vs 27.5%), 3 (10.6% vs 19.7%), 4 (5.6% vs 3.4%), or at least 5 (4.4% vs 3.9%). Most patients had intra-abdominal metastases at 85.0% vs 87.1%, respectively.

Regarding prior therapy, most patients had received 2 prior regimens (46.7% vs 44.4% in the combination vs chemotherapy arms, respectively), with the next highest being 3 (30.0% vs 30.3%). The highest number of prior regimens was 4 (1.7% vs 1.1%). About one-third of patients in each arm had prior PARP inhibitor use and about 80% had prior bevacizumab use.

Of the 358 patients enrolled, 180 were randomized to alpelisib plus olaparib and 178 were assigned to chemotherapy, which consisted of physician's choice of paclitaxel or pegylated liposomal doxorubicin.

The primary end point was PFS (RECIST 1.1), with secondary end points including ORR, duration of response, and OS. The data cutoff date was April 21, 2023.

Olaparib has several FDA-approved indications in ovarian cancer. Alpelisib is not approved for use in ovarian cancer but does have an FDA approval for use in combination with fulvestrant in the second-line setting for patients with hormone receptor–positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer.

In a commentary published with the article, JCO Associate Editor Gini F. Fleming, MD, discussed the relevance of the study results.

“This phase 3 trial, one product of many attempts to ‘sensitize’ ovarian cancers to PARP inhibitors, showed no evidence that alpelisib plus olaparib was superior to [treatment of physician’s choice], and re-demonstrated the dismal PFS (3.6 v 3.9 months) overall for women with platinum-resistant ovarian cancer,” wrote Fleming.¹ 

REFERENCES:

1. Konstantinopoulos PA, Kim JW, Freyer G, et al. Primary analysis of EPIK-O/ENGOT-ov61: Alpelisib plus olaparib versus chemotherapy in platinum-resistant or platinum-refractory high-grade serous ovarian cancer without BRCA mutation. J Clin Oncol. 2025;43(??):1-10. doi:10.1200/JCO-25-00225.

2. EPIK-O: A Phase III, Multi-center, Randomized (1:1), Open-label, Active-controlled, Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Olaparib as Compared to Single Agent Cytotoxic Chemotherapy, in Participants With No Germline BRCA Mutation Detected, Platinum-resistant or -Refractory, High-grade Serous Ovarian Cancer. ClinicalTrials.gov Identifier: NCT04729387. Last updated February 12, 2025. Accessed August 14, 2025. https://clinicaltrials.gov/study/NCT04729387