Olaparib Leads PARP Inhibitors in Boosting OS for Platinum-Sensitive Recurrent Ovarian Cancer

While all poly ADP-ribose polymerase (PARP) inhibitors have demonstrated improvements in progression-free survival (PFS), only olaparib prolonged overall survival (OS), according to a recently published review, indicating it may be the preferred option for patients with platinum-sensitive recurrent ovarian cancer (PSROC).¹

The authors of the Journal of Ovarian Research study explained that PARP inhibitors have recently demonstrated efficacy in treating patients with ovarian cancer, especially when used for maintenance treatment of PSROC. This treatment method exploits faulty DNA repair mechanisms through synthetic lethality, which leads to genomic instability and tumor cell death.²

The FDA has approved PARP inhibitors olaparib, rucaparib, and niraparib to treat patients with ovarian cancer, and they are recommended as maintenance therapy for PSROC by both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).¹ Also, fuzuloparib was approved for the maintenance treatment of PSROC in China.

Previous studies have verified the impact of the 3 FDA-approved PARP inhibitors on enhancing PFS in patients with recurrent OC. However, analyses of OS are lacking due to insufficient follow-up time, and pooled analyses of other survival outcomes remain scarce. Additionally, the efficacy and safety of fuzuloparib compared with that of the other 3 PARP inhibitors have not been fully reported.

While all poly ADP-ribose polymerase (PARP) inhibitors improved progression-free survival, olaparib significantly extended overall survival (OS), making it a preferred option. | Image Credit: Queenmoonlite Studio - stock.adobe.com

Consequently, the researchers performed a network meta-analysis on these 4 PARP inhibitors regarding survival outcomes and adverse effects. The main outcome measure was OS, while the secondary goals were the following survival outcomes: PFS, second PFS (PFS2), time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), and chemotherapy-free interval (CFI).

The researchers also compared the safety outcomes among the PARP inhibitors, including grade 3 to 4 treatment-emergent adverse events (TEAEs), TEAEs leading to treatment discontinuation, and hematological TEAEs; as evaluated by the Common Terminology Criteria for Adverse Events (CTCAE), grade 3 to 4 adverse outcomes indicate severe and potentially fatal toxicity.

Two researchers independently searched various databases for eligible studies published by January 6, 2024. They initially identified 4556 potential studies but ultimately analyzed 6 randomized controlled trials (RCTs), containing 2194 patients. The researchers gathered essential content from the RCTs, including the therapeutic medicines used, median follow-up period, and frequency of adverse events.

All 6 RCTs compared PFS data among the 4 PARP inhibitors. Compared with placebo, fuzuloparib (HR, 0.25; 95% CI, 0.16-0.40), olaparib (HR, 0.32; 95% CI, 0.24-0.43), niraparib (HR, 0.35; 95% CI, 0.27-0.45), and rucaparib (HR, 0.37; 95% CI, 0.27-0.52) contributed to a statistically significant PFS benefit. The researchers determined that fuzuloparib would most likely provide the greatest PFS benefit, followed by olaparib, niraparib, and rucaparib.

Additionally, 5 of the RCTs provided OS data. Two of these trials contained groups treated with olaparib, 2 had groups treated with niraparib, and 1 included a group treated with rucaparib. Olaparib was the only PARP inhibitor found to significantly decrease overall death (HR, 0.73; 95% CI, 0.60-0.90) as no significant difference was found among those treated with niraparib (HR, 0.94; 95% CI, 0.78-1.13) or rucaparib (HR, 1.00; 95% CI, 0.81-1.22). Therefore, only olaparib achieved efficacy on OS.

Regarding the other outcomes, 4 RCTs reported data on CFI, indicating that fuzuloparib (HR, 0.30; 95% CI, 0.15-0.62), niraparib (HR, 0.36; 95% CI, 0.25-0.53), and rucaparib (HR, 0.43; 95% CI, 0.24-0.76) provided significant benefits for this patient population. Also, 3 RCTs suggested that olaparib (HR, 0.50; 95% CI, 0.34-0.73), rucaparib (HR, 0.70; 95% CI, 0.58-0.85), and niraparib (HR, 0.75; 95% CI, 0.61-0.93) improved PFS2 compared with placebo.

In the TFST analysis, data from 5 RCTs indicated that olaparib (HR, 0.38; 95% CI, 0.28-0.52), niraparib (HR, 0.40; 95% CI, 0.31-0.54), and rucaparib (HR, 0.43; 95% CI, 0.29-0.64) showed a notable benefit over the placebo. Similarly, in the TSST analysis, 3 RCTs reported that olaparib (HR, 0.52; 95% CI, 0.43-0.63) and rucaparib (HR, 0.68; 95% CI, 0.54-0.85) demonstrated superior outcomes.

As for safety outcomes, treatment with olaparib (OR, 2.40; 95% CI, 1.56-3.70), niraparib (OR, 3.06; 95% CI, 2.42-3.87), rucaparib (OR, 3.76; 95% CI, 2.68-5.28), and fuzuloparib (OR, 4.47; 95% CI, 2.36-8.46) was associated with a numerically higher risk of grade 3 to 4 TEAEs compared with placebo. However, olaparib had the lowest incidence of grade 3 to 4 hematological TEAEs among the PARP inhibitors.

The researchers acknowledged their study’s limitations, including the number of studies analyzed. Consequently, they emphasized the need for further research to strengthen their findings, identifying key areas for investigation.

“The safety profile helps to enhance confidence in promoting PARP inhibitors, but long-term monitoring and evaluation of safety are still required,” the authors wrote. “…with the widespread use of PARP inhibitors in first-line treatment of OC, whether benefit continues in second or later line treatment needs further investigation.”

References

1. Ji S, Chen L, Yu Y, et al. A comprehensive comparison of PARP inhibitors as maintenance therapy in platinum-sensitive recurrent ovarian cancer: a systematic review and network meta-analysis. J Ovarian Res. 2025;18(1):18. doi:10.1186/s13048-025-01599-1
2. Javle M, Curtin NJ. The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011;105(8):1114-1122. doi:10.1038/bjc.2011.382