Ovarian cancer remains a formidable challenge in oncology, particularly due to its high recurrence rates and limited treatment options. PSR disease poses a specific clinical challenge, with the need for effective maintenance therapy to prolong PFS and delay recurrence. In recent years, the emergence of PARP inhibitors, such as olaparib and niraparib, has revolutionized the management of recurrent epithelial ovarian cancer, offering new hope for patients. Our retrospective study adds to the growing body of evidence supporting the efficacy of PARP inhibitors in PSR ovarian cancer. We found that maintenance therapy with PARP inhibitors significantly prolonged mean PFS compared to observation alone, regardless of BRCA mutation status. This finding aligns with previous clinical trials demonstrating the efficacy of PARP inhibitors in PSR disease, with improvements in PFS observed in both BRCA-mutated and non-BRCA-mutated patients.
Furthermore, our subgroup analysis comparing olaparib and niraparib revealed no statistically significant difference in PFS between the two drugs. This suggests that both olaparib and niraparib confer similar benefits in terms of prolonging the platinum-free interval in PSR ovarian cancer, supporting the notion that they share a common mechanism of action targeting PARP. This mechanism involves competitive inhibition at the PARP active site by nicotinamide adenine dinucleotide (NAD+), thereby inhibiting the synthesis of poly(ADP-ribose) polymers [12]. Inhibitors binding to the NAD + site on PARP1 and PARP2 induce conformational changes, stabilizing the PARP-DNA complex and thus “trapping” it to prolong its cellular presence and impede DNA repair [13, 14].
Interestingly, our study has unveiled a notable finding that challenges the current paradigm regarding the use of PARP inhibitors in PSR ovarian cancer. Contrary to the 2024 NCCN guidelines, which recommend PARP inhibitors solely for patients with BRCA-mutated PSR disease, our data suggest a broader efficacy profile for these agents. Specifically, we observed that BRCA mutation status did not significantly influence the efficacy of PARP inhibitors in terms of PFS. Our findings resonate with previous studies demonstrating the efficacy of PARP inhibitors beyond BRCA-mutated cohorts. For instance, the SOLO-2 study demonstrated that olaparib significantly extended median PFS over placebo (19.1 vs. 5.5 months; HR 0.30; P < 0.0001) and provided a substantial overall survival (OS) advantage of 12.9 months, confirming its sustained efficacy in PSR epithelial ovarian cancer patients with germline BRCA mutations [15]. Subsequent OPINION study confirmed olaparib’s effectiveness in extending median PFS (9.2 months, 95% CI 7.6–10.9) and OS (32.7 months, 95% CI 29.5–35.3) in a broader cohort, regardless of BRCA mutation status [16]. Similarly, the NOVA study revealed niraparib’s ability to significantly extend median PFS in comparison to placebo, both in PSR epithelial ovarian cancer patients with a gBRCA mutation (21.0 vs. 5.5 months; HR 0.27; P < 0.001) and those without (9.3 vs. 3.9 months; HR 0.45; P < 0.001) [17, 18]. Although the NOVA study did not demonstrate an extension in OS for patients without gBRCA mutations, recent findings from the NORA study in the Chinese population demonstrated a decreased mortality risk with niraparib, irrespective of BRCA mutation status [19]. The discrepancy between guideline recommendations and real-world evidence emphasizes the necessity for further research to determine the optimal use of PARP inhibitors in PSR ovarian cancer. In addition to BRCA mutation status, which has been a significant focus in understanding patient outcomes, future research should explore a broader range of predictive biomarkers to enhance personalized treatment strategies. For instance, multi-omics analyses, such as whole-genome sequencing and targeted gene panels [20], could reveal novel genetic alteration. Additionally, assessing HRD status through genomic instability scoring could provide further predictive value [21].
In the niraparib arm, it is noteworthy that although not reaching statistical significance, there was a trend towards longer mean PFS in the BRCA wild-type subgroup compared to the BRCA mutation subgroup, which contrasts with findings from the NOVA study [8]. This observation becomes particularly striking when comparing subgroups receiving olaparib and niraparib. In the niraparib group, the mean PFS for patients with BRCA mutations was 16.0 months, whereas in the olaparib group, the mean PFS for the same subgroup was substantially longer at 27.5 months. Despite a statistically significant difference, the olaparib group exhibited a notably longer average PFS in the presence of BRCA mutations. The discrepancies between our study findings and the guidelines may be attributed to the several reasons. Firstly, our study population may differ from those included in the guideline studies in terms of patient characteristics, disease stage, or treatment history. Differences in study design, including variations in data collection methods, endpoints, and statistical analyses could also contribute to the observed discrepancies. While our findings, grounded in real-world data, provide valuable insights. It’s important to acknowledge that our patient cohort may be relatively small as it was derived from a single center, a large-scale research is imperative to validate and elucidate the significance of such observations which might inform future revisions or adaptations of clinical practices. Moreover, due to variability in patient enrollment times, comprehensive OS data for all participants are currently unavailable. All patients are still being monitored, and further OS data will be included in future studies.
In conclusion, our study reinforces the importance of PARP inhibitors as standard maintenance therapy for PSR ovarian cancer, irrespective of BRCA mutation status. Both olaparib and niraparib demonstrate efficacy in prolonging PFS, underscoring their role as valuable treatment options in the management of recurrent epithelial ovarian cancer. Further research is warranted to refine patient selection criteria and optimize the use of PARP inhibitors in clinical practice.
Add Comment