Multi-Trial Analysis Reveals Disconnect Between PFS and OS in Ovarian Cancer

Findings of a comprehensive systematic review and meta-analysis on the use of PARP inhibitor maintenance therapy for patients with advanced-stage epithelial ovarian cancer following first-line platinum-based chemotherapy found that there was significant disconnect between progression-free survival (PFS) and overall survival (OS).¹

The analysis synthesized data from 7 randomized clinical trials involving 4013 patients (2619 receiving a PARP inhibitor and 1394 receiving standard of care alone).

While PARP inhibitor maintenance therapy is associated with a clear improvement in PFS for the overall patient population and most molecular subgroups, this benefit did not translate into a statistically significant improvement in OS for any subgroup. Furthermore, treatment was associated with a significantly increased risk of high-grade adverse events (AEs).

Overall Population Outcomes: PFS Benefit Without OS Improvement

In the total patient population, PARP inhibitor maintenance demonstrated a clear and statistically significant improvement in delaying disease progression but failed to show a corresponding benefit in OS.

PFS wasassociated with a 43% reduction in the hazard of progression or death (HR, 0.57; 95% CI, 0.46–0.70).

OS was notsignificantly different from standard of care alone (HR, 0.94; 95% CI, 0.66–1.34).

Efficacy Across Molecular Subgroups

The benefit of PARP inhibitors varied significantly based on the tumor's molecular profile, particularly its homologous recombination repair capability. While patients with deficiencies in this pathway benefit most in terms of PFS, no group achieved a statistically significant OS benefit.

Efficacy Across Clinical Scenarios

The PFS benefit associated with PARP inhibitors was found to be consistent across various clinical situations, reinforcing their broad applicability for delaying recurrence.

Improved PFS was seen in patients with both a complete response (HR, 0.50) and a partial response (HR, 0.57) to initial chemotherapy.

Improved PFS was observed regardless of whether patients underwent primary cytoreductive surgery (HR, 0.54) or neoadjuvant chemotherapy followed by surgery (HR, 0.51).

Improved PFS was found in patients with both optimal (complete) cytoreduction (HR, 0.51) and suboptimal (incomplete) cytoreduction (HR, 0.39).

Comparative Analysis of PARP Inhibitor Regimens

While no trials directly compared different PARP inhibitors, the meta-analysis performed a descriptive comparison based on each drug's performance against standard –of care. This revealed significant variability in both efficacy and safety.

Senaparib (IMP4297) demonstrated the lowest observed risk ratio for recurrence or death in the overall population (RR, 0.53). Veliparib (ABT-888) showed the lowest observed risk ratio among patients with BRCA-variant tumors. Olaparib (Lynparza) had the highest risk ratio among the agents analyzed (RR, 0.83), indicating a comparatively smaller effect size in its trial.

Niraparib (Zejula) showed the highest risk of grade ≥3 AEs (RR, 4.73; 95% CI, 2.77–8.07). Veliparib (RR, 1.15; 95% CI, 0.64–2.06) and olaparib (RR, 1.34; 95% CI, 0.87–2.08) showed the lowest risk for high-grade toxic AEs.

Implications and Limitations

The variability in efficacy and toxicity across both patient subgroups and specific PARP inhibitors highlights that treatment decisions should not be uniform. The balance between a PFS benefit, increased AEs, and the lack of an OS benefit must be carefully considered for each patient.

The lack of correlation between PFS and OS suggests that PFS alone may not be a sufficient primary end point for maintenance therapies. Future studies are encouraged to prioritize mature OS data and patient-centered outcomes like quality-adjusted survival.

The findings underscore the importance of refining patient stratification beyond current BRCA and homologous recombination deficiency testing to better identify who will truly benefit from PARP inhibitor maintenance.

The authors acknowledge several limitations, including the lack of direct head-to-head trials comparing PARP inhibitors, limited availability of mature OS data for some trials, and inconsistent reporting of AEs and quality-of-life outcomes across studies.

“Varying efficacy and safety profiles of different PARP inhibitor regimens in different clinical and molecular populations, coupled with the increased incidence of [AEs], emphasize the importance of personalized treatment strategies,” concluded Petousis S et al, authors of the study. “Future research should prioritize refining patient stratification through advanced biomarker identification and assess quality-adjusted survival as the primary outcome for maintenance therapies.”

REFERENCE

1.Petousis S, Kahramanoglu I, Appenzeller-Herzog C, et al. PARP inhibitor maintenance after first-line chemotherapy in advanced-stage epithelial ovarian cancer: A systematic review and meta-analysis. JAMA Netw Open. 2025;8(11):e2541648. doi:10.1001/jamanetworkopen.2025.41648