Highlight
- The combination of alpelisib (a PI3K inhibitor) plus olaparib (a PARP inhibitor) did not improve progression-free survival (PFS) compared to chemotherapy in platinum-resistant/refractory high-grade serous ovarian cancer (HGSOC) patients without BRCA mutation.
- Overall response rates (ORR) and overall survival (OS) were comparable between the experimental combination and physician’s choice chemotherapy arms.
- Safety profiles were consistent with known adverse events of both agents, with no new safety signals observed.
- Biomarker analyses provided exploratory insights into molecular subsets of responders, suggesting potential future avenues for patient selection.
Study Background and Disease Burden
High-grade serous ovarian cancer (HGSOC) is among the most aggressive epithelial ovarian cancers, notorious for its poor prognosis especially in the platinum-resistant or platinum-refractory setting. Platinum resistance, defined as progression within 6 months of platinum-based therapy, drastically limits effective treatment options and survival outcomes.
PARP inhibitors have shown remarkable activity in patients with germline or somatic BRCA mutations, exploiting homologous recombination deficiency (HRD). However, the majority of patients without BRCA mutations (wild type) derive less benefit, and alternative strategies to improve outcomes are urgently needed. Alpelisib, a selective PI3K-alpha inhibitor, targets a pathway frequently altered in ovarian cancers, potentially sensitizing tumors to PARP inhibition. The EPIK-O trial was designed to assess whether combining alpelisib with olaparib could improve outcomes in patients with platinum-resistant/refractory HGSOC lacking BRCA mutations.
Study Design
EPIK-O was an open-label, international, phase III randomized controlled trial enrolling 358 patients with platinum-resistant or platinum-refractory HGSOC who had no known germline or somatic BRCA mutation. Eligible patients had received 1 to 3 prior systemic therapies, and prior bevacizumab treatment was encouraged unless contraindicated. Prior PARP inhibitor exposure was permitted.
Patients were randomized 1:1 to receive:
- Alpelisib 200 mg orally once daily plus olaparib 200 mg orally twice daily, or
- Treatment of physician’s choice (TPC), consisting of single-agent paclitaxel (80 mg/m2 once weekly) or pegylated liposomal doxorubicin (PLD, 40–50 mg/m2 once every 28 days).
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review using RECIST 1.1 criteria. Secondary endpoints included overall response rate (ORR), duration of response (DOR), overall survival (OS), and safety.
Key Findings
With a median follow-up of 9.3 months, 180 patients received alpelisib plus olaparib and 178 received TPC. At data cutoff, 18.3% and 16.9% respectively remained on treatment.
Primary endpoint: Median PFS was 3.6 months for the combination arm versus 3.9 months for TPC (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.88 to 1.48; one-sided p = 0.84), indicating no statistically significant improvement with alpelisib plus olaparib.
Secondary endpoints:
- Overall response rate was 15.6% (95% CI 10.6%–21.7%) with the combination versus 13.5% (95% CI 8.8%–19.4%) with chemotherapy, showing minimal difference.
- Median overall survival was 10.0 months versus 10.6 months (HR 1.22; 95% CI 0.87 to 1.71), similarly demonstrating no OS benefit.
Safety: The safety profile of alpelisib plus olaparib was consistent with known toxicities of individual agents—common adverse events included hyperglycemia (alpelisib-related) and anemia or gastrointestinal disturbances (olaparib-related). No new or unexpected safety signals emerged.
Biomarker analyses suggested potential subgroups who might benefit from PI3K pathway inhibition combined with PARP inhibition, though these exploratory findings require validation in future studies.
Expert Commentary
The EPIK-O trial highlights the ongoing challenges in treating platinum-resistant or refractory HGSOC without BRCA mutations, where limited effective therapies exist. Despite strong biological rationale for PI3K inhibition to enhance PARP inhibitor sensitivity, this combination did not translate into clinically meaningful PFS or OS improvements compared with standard chemotherapy.
Potential reasons include the complex tumor microenvironment and diverse resistance mechanisms beyond PI3K pathway alterations in these tumors. Additionally, prior bevacizumab and allowance of previous PARP inhibitors may have affected therapeutic responses. The modest ORR and short PFS underline the aggressive nature of this patient population.
Notably, these findings align with the broader experience that PARP inhibitor benefit is more robust in BRCA-mutant or HRD-positive settings, emphasizing the need for precise patient selection and novel combinatorial strategies in BRCA wild-type populations.
Future research may focus on integrating molecular biomarkers identified in EPIK-O to prospectively select patients, as well as combining PI3K and PARP inhibitors with other agents such as immune checkpoint inhibitors or anti-angiogenics.
Conclusion
The phase III EPIK-O trial demonstrated that adding alpelisib to olaparib did not improve progression-free survival, overall response, or overall survival compared to chemotherapy in platinum-resistant or platinum-refractory high-grade serous ovarian cancer patients without BRCA mutations. Safety profiles were manageable and consistent with known drug effects.
This study underscores the difficulty of developing effective targeted treatments in this challenging clinical scenario. Biomarker insights from EPIK-O may inform future personalized therapy approaches. Until then, chemotherapy remains a standard of care, highlighting an unmet need for innovative treatments in this patient subset.
References
Konstantinopoulos PA, Kim JW, Freyer G, Lee JY, Gaba L, Grisham RN, 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 Sep 10;43(26):2908-2917. doi: 10.1200/JCO-25-00225. Epub 2025 Jul 23. PMID: 40700681.
Lheureux S, Mukhopadhyay A, Kanis M, et al. PARP inhibition in ovarian cancer: Molecular mechanisms, clinical relevance and future strategies. Nat Rev Clin Oncol. 2022;19(7):514–532. doi:10.1038/s41571-022-00612-3
Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Newly Diagnosed Ovarian Cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. doi:10.1056/NEJMoa1105535
