EPIK-O and beyond: PI3Kα inhibition plus PARP blockade in platinum-resistant BRCA-wildtype ovarian cancer
Editorial Commentary

EPIK-O and beyond: PI3Kα inhibition plus PARP blockade in platinum-resistant BRCA-wildtype ovarian cancer

Mali Barbi1,2 ORCID logo, Divya Bhana3, Veena S. John1 ORCID logo

1Northwell Health Cancer Institute, New Hyde Park, NY, USA; 2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, New Hyde Park, NY, USA

Correspondence to: Veena S. John, MD. Northwell Health Cancer Institute, 450 Lakeville Rd, New Hyde Park, NY 11042, USA. Email: vjohn@northwell.edu.

Comment on: 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;43:2908-17.

Keywords: Platinum-resistant ovarian cancer (PROC); BRCA-wildtype; PARP inhibitors; PI3K pathway

Received: 26 September 2025; Accepted: 26 February 2026; Published online: 17 June 2026.

doi: 10.21037/actr-25-109

Introduction

Platinum-resistant ovarian cancer (PROC) carries a poor prognosis and limited treatment options (1,2). The standard of care in this setting is sequential use of single-agent chemotherapy with weekly paclitaxel, pegylated liposomal doxorubicin, topotecan, or gemcitabine, which achieve response rates of only 10–15% and are associated with short progression-free survival (PFS) (3-6). In the phase III AURELIA trial, the addition of bevacizumab to single agent chemotherapy improved median PFS from 3.4 to 6.7 months, but durable control was uncommon, highlighting the persistent unmet need in PROC (7).

The therapeutic landscape for patients with PROC is evolving. Recently, the role of antibody-drug conjugates (ADCs) has expanded significantly; for instance, mirvetuximab soravtansine has emerged as a standard for folate receptor alpha (FRα)-high tumors (8). Furthermore, while immunotherapy has transformed outcomes in many solid tumors, its role in PROC remains under investigation, with recent studies exploring combinations of immune checkpoint inhibitors to overcome the immunosuppressive tumor microenvironment (9). Despite these advances, effective options for the broad population of patients, particularly those with BRCA-wildtype disease, remain scarce.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown anti-tumor activity as maintenance therapy in platinum-sensitive ovarian cancer with germline or somatic BRCA1/2 mutations or other homologous recombination deficiency (HRD). However, in PROC, single-agent PARPi are not recommended. Their efficacy has been minimal, with overall response rates (ORRs) under 5% in BRCA-wildtype disease and only limited benefit in patients with germline or somatic BRCA mutations (10,11).

To overcome these limitations, combination strategies have been pursued, aiming to induce HRD and extend the benefit of PARPi. Anti-angiogenic combinations with cediranib plus olaparib improved PFS in the phase II BAROCCO trial (5.6 vs. 3.1 months with paclitaxel) and achieved a 50% response rate in HRD-positive disease in AMBITION, but efficacy dropped to 9% in the EVOLVE trial after prior PARPi (12-14). Immunotherapy combinations have also shown modest activity: niraparib plus pembrolizumab achieved an 18% ORR in PROC irrespective of BRCA status in TOPACIO/KEYNOTE-162 (15).

Cell-cycle checkpoint combinations have also been evaluated. ATR inhibition with ceralasertib plus olaparib produced no responses in PARPi-naïve PROC (16). CHK1 inhibition with prexasertib plus olaparib achieved a 22% ORR in BRCA1/2-mutated, PARPi-resistant disease (17). WEE1 inhibition with adavosertib plus olaparib improved ORR to 29% compared with 23% for adavosertib alone in the phase II EFFORT trial, with high rates of disease control but overlapping toxicities (18). Most recently, the randomized phase II NRG-GY023 trial tested durvalumab, olaparib, and cediranib triplets or doublets versus chemotherapy in bevacizumab-pretreated PROC; all experimental arms failed to improve PFS, with modest ORRs of 9–16% (19). Collectively, these studies show that while some combinations demonstrate anti-tumor activity, none have produced durable benefit in PROC (Table 1).

Table 1

Clinical trials evaluating targeted therapy and immunotherapy in ovarian cancer

Clinical trial Subgroups Regimens PFS (months) ORR HR P value
Zamarin et al. (20) Platinum free interval <6 months vs. 6–12 months Nivolumab vs. nivolumab plus ipilimumab 2.0 vs. 3.9 12.2% vs. 31.4% 0.53 (95% CI: 0.34–0.82) 0.004 (PFS)
Matulonis et al. (21) Platinum free interval 3–12 months with 1–3 prior lines of treatment vs. >3 months interval with 4–6 prior lines of treatment Pembrolizumab 2.1 vs. 2.1 8.0% overall; 17% if PD-L1 CPS >10 – –
Konstantinopoulos et al. (15) – Niraparib plus pembrolizumab Not reported 18% – –
Lheureux et al. (22) – Adavosertib (WEE1) plus gemcitabine vs. gemcitabine plus placebo 4.6 vs. 3.0 NR 0.55 (95% CI: 0.35–0.90) 0.015
Matulonis et al. (23) FRα-high, 1–3 prior lines, prior bevacizumab Mirvetuximab soravtansine (FRα) vs. investigator’s choice chemotherapy 5.6 vs. 3.9 42.3% vs. 15.9% 0.63 (95% CI: 0.49–0.81) <0.001
Konstantinopoulos et al. (24) – Berzosertib (ATR) plus gemcitabine vs. gemcitabine 5.3 vs. 3.4 NR 0.57 (90% CI: 0.33–0.98) 0.044
Konstantinopoulos et al. (25,26) Platinum-resistant or refractory, 1–3 prior lines, prior bevacizumab Alpelisib plus olaparib vs. investigator’s choice chemotherapy 3.6 vs. 3.9 15.6% vs. 13.5% 1.14 (95% CI: 0.88 to 1.48) 0.84

This table summarizes key studies investigating targeted and immune-based agents in ovarian cancer, including subgroups that were studied, regimens of interest, PFS and ORR. ATR, ataxia telangiectasia and Rad3-related protein; CI, confidence interval; CPS, combined positive score; FRα, folate receptor alpha; HR, hazard ratio; NR, not reported; ORR, overall response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival.

The EPIK-O trial

In this context, the phase III EPIK-O/ENGOT-OV61 trial, tested whether inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway could sensitize BRCA-wildtype, PROC to PARP inhibition. The rationale was based on preclinical studies showing that PI3K inhibition downregulates BRCA1/2 expression, impairs RAD51 recruitment, and disrupts nucleotide metabolism, thereby inducing HRD and increasing susceptibility to PARPi (27,28). A preceding phase Ib study of alpelisib plus olaparib reported an ORR of 31% in patients with BRCA-wt, PROC, providing justification for the phase III investigation (25).

EPIK-O was a multicenter, open-label, randomized phase III-controlled trial. A total of 358 women with BRCA-wt, platinum-resistant or refractory ovarian cancer were randomized 1:1 to receive alpelisib plus olaparib versus investigator’s choice of weekly paclitaxel or PLD. The primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety. The trial did not meet its primary endpoint. Median PFS was 3.6 months with alpelisib/olaparib compared with 3.9 months with chemotherapy [hazard ratio (HR) =1.14; 95% confidence interval (CI): 0.88–1.48; P=0.84]. ORR was 15.6% with the combination versus 13.5% in the control arm, and median overall survival (OS) was approximately 10 months in both groups (26). Safety was consistent with the known toxicity profiles of alpelisib and olaparib, though higher rates of discontinuation occurred in the experimental arm due to hyperglycemia, gastrointestinal toxicity and rash.

Strengths, limitations, and future trial design

The EPIK-O trial had several strengths, including a strong biological rationale supported by preclinical evidence of “contextual synthetic lethality” and a rigorous randomized design comparing a novel chemotherapy-free doublet against the standard of care in a difficult-to-treat population. However, the study faced significant limitations. The poorer outcomes observed likely reflect population differences and the lack of precise biomarkers. EPIK-O enrolled a heavily pretreated population, 80% had prior bevacizumab and 35% prior PARPi, compared with none in the phase Ib study (25) and included more patients with platinum-resistant rather than partially sensitive disease. These differences in patient population highlight the challenge of translating early-phase signals into late-phase success.

Biomarker and correlative insights

Correlative analyses from EPIK-O suggested a signal of benefit in tumors with PI3K pathway alterations and HRD-negative status, indicating molecular heterogeneity within this group. This raises the possibility that PI3K activation may define a therapeutically vulnerable subset beyond conventional HRD classification. Incorporating PI3K status alongside HRD testing could refine patient selection. Yet, the modest efficacy observed overall highlights redundancy within the PI3K/AKT axis. Preclinical studies have shown that AKT2 promotes tumor survival and resistance, potentially limiting the impact of PI3Kα inhibition in ovarian cancer (29,30). Collectively, these findings point to the need for biomarker-enriched studies that integrate PI3K pathway status while also addressing AKT2 as a therapeutic target.

New horizons: the ROSELLA trial

While EPIK-O demonstrated the challenges of sensitizing agents, other strategies targeting resistance mechanisms have shown promise. The phase III ROSELLA trial evaluated relacorilant, a selective glucocorticoid receptor (GR) modulator, in combination with nab-paclitaxel. This approach targets the cortisol-driven anti-apoptotic pathways that contribute to chemoresistance. The trial demonstrated a statistically significant improvement in PFS (median 6.5 vs. 5.5 months; HR =0.70) and a trend toward improved OS HR (interim): 0.69 (95% CI 0.52–0.92) compared to nab-paclitaxel alone (31). Unlike EPIK-O, ROSELLA succeeded by targeting a resistance mechanism (GR modulation) that appears relevant across a broader, unselected population of platinum-resistant patients.

Conclusions

The EPIK-O/ENGOT-OV61 trial did not demonstrate superiority of alpelisib plus olaparib over chemotherapy in BRCA-wt PROC. However, it clarified the limits of PI3Kα inhibition and generated correlative data that may guide biomarker-driven strategies. Progress will depend on molecularly defined patient selection and rational combinations that address both DNA repair and downstream survival mechanisms such as AKT2, with newer modalities to improve outcomes in this difficult-to-treat disease. Further clinical trial-based research is necessary to investigate mechanisms of response and resistance, elucidate optimal dosing, and identify predictive biomarkers. Utilizing these translational insights to guide regimen selection may result in more meaningful clinical outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-109/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-109/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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doi: 10.21037/actr-25-109
Cite this article as: Barbi M, Bhana D, John VS. EPIK-O and beyond: PI3Kα inhibition plus PARP blockade in platinum-resistant BRCA-wildtype ovarian cancer. AME Clin Trials Rev 2026;4:25.

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