Academic Background

Ovarian cancer is one of the most common malignancies of the female reproductive system. Despite recent advancements in treatment, the recurrence rate remains high, particularly in patients with late relapse. Platinum-based chemotherapy (CT) is the standard treatment for ovarian cancer, and poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy have shown significant clinical benefits in platinum-sensitive patients. However, although PARP inhibitors have succeeded in prolonging progression-free survival (PFS), further improving treatment outcomes remains a focus of clinical research.

In recent years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in various solid tumors, especially in PD-L1-positive patients. However, in ovarian cancer, despite a strong preclinical rationale, multiple phase III clinical trials have failed to show that PD-L1 inhibitors (such as atezolizumab or avelumab) combined with chemotherapy or bevacizumab can significantly improve patient outcomes. Therefore, researchers have begun exploring the potential of combining immune checkpoint inhibitors with PARP inhibitors to achieve breakthroughs in ovarian cancer treatment.

Study Source

This study was conducted by Antonio González-Martín and colleagues from multiple European research institutions, primarily including the Spanish Gynecological Cancer Research Group (Grupo Español de Investigación en Cáncer Ginecológico, GEICO) and the European Network for Gynaecological Oncological Trial Groups (ENGOT). The study was published on September 18, 2024, in the Journal of Clinical Oncology, titled “Atezolizumab Combined with Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer with a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.”

Study Process

Study Design

This was a global, multicenter, randomized, double-blind, placebo-controlled phase III clinical trial aimed at evaluating the efficacy of atezolizumab combined with platinum-based chemotherapy and maintenance therapy with niraparib in patients with late-relapsing recurrent ovarian cancer. The study enrolled patients who had previously received 1-2 lines of chemotherapy (the most recent treatment included platinum) and had a treatment-free interval since last platinum (TFIP) of >6 months. Patients were stratified based on the investigator-selected carboplatin doublet, TFIP, BRCA status, and PD-L1 status, and were randomly assigned to the atezolizumab or placebo group. All patients received six cycles of carboplatin doublet chemotherapy, followed by maintenance therapy with niraparib in patients with stable or responsive disease until disease progression.

Study Population

The study enrolled 417 patients, of whom 15% had BRCA mutations, 36% were PD-L1 positive, and 66% had a TFIP >12 months. The median follow-up was 28.6 months. The primary endpoint was investigator-assessed PFS, and secondary endpoints included objective response rate (ORR), PFS during maintenance therapy, and others.

Experimental Methods

Before randomization, investigators selected a carboplatin doublet regimen for each patient, including carboplatin combined with paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD). Patients were randomly assigned to the atezolizumab or placebo group and received six cycles of carboplatin doublet chemotherapy combined with atezolizumab or placebo. After completing chemotherapy, patients with stable or responsive disease continued maintenance therapy with niraparib until disease progression.

Data Analysis

The primary endpoint, PFS, was analyzed using a stratified Cox proportional hazards model, and the Kaplan-Meier method was used to estimate median PFS and its 95% confidence interval (CI). Efficacy analysis was conducted in the intention-to-treat (ITT) population, and safety analysis was performed in the safety-evaluable population.

Main Results

The study results showed that the median PFS was 11.2 months (95% CI, 10.1-12.1 months) in the atezolizumab group and 10.1 months (95% CI, 9.2-11.2 months) in the placebo group, with no statistically significant difference between the two groups (HR=0.89, 95% CI, 0.71-1.10; p=0.28). Subgroup analyses showed that PD-L1 status, BRCA status, and other factors did not significantly affect the efficacy of atezolizumab. Additionally, the ORR was 45% (95% CI, 39-52%) in the atezolizumab group and 43% (95% CI, 36-49%) in the placebo group, with no statistically significant difference between the two groups.

During the maintenance therapy period, the median PFS was 6.7 months (95% CI, 5.3-8.3 months) in the atezolizumab group and 5.3 months (95% CI, 4.3-6.1 months) in the placebo group, with no statistically significant difference between the two groups (HR=0.80, 95% CI, 0.62-1.03).

Conclusion

This study demonstrated that atezolizumab combined with platinum-based chemotherapy and niraparib maintenance therapy did not significantly improve PFS or ORR in patients with late-relapsing recurrent ovarian cancer. Although a certain prolongation of PFS was observed during the maintenance therapy period, this difference was not statistically significant. The safety data were consistent with previous experience, and no new safety signals were identified.

Study Highlights

1. First Evaluation of Immune Checkpoint Inhibitor Combined with PARP Inhibitor: This study is the first phase III clinical trial to evaluate atezolizumab combined with platinum-based chemotherapy and niraparib maintenance therapy in late-relapsing recurrent ovarian cancer.
2. Extensive Subgroup Analysis: The study analyzed multiple subgroups, including PD-L1 status and BRCA status, and the results showed that the efficacy of atezolizumab was not significantly superior to placebo in any subgroup.
3. Safety Data Consistent with Previous Experience: The safety data were consistent with previous experience with atezolizumab and niraparib, and no new safety signals were identified.

Study Significance

Although this study did not demonstrate significant efficacy of atezolizumab in late-relapsing recurrent ovarian cancer, it provides important references for future research. Particularly in the context of combining immune checkpoint inhibitors with PARP inhibitors, the results of this study suggest that relying solely on immune checkpoint inhibitors may not be sufficient to significantly improve outcomes in ovarian cancer patients. Future research may need to further explore other combination therapies or biomarkers to identify patient populations that may benefit from immunotherapy.

Other Valuable Information

The limitations of this study include the fact that, although extensive subgroup analyses were conducted, some subgroups (e.g., BRCA-mutated patients) had small sample sizes, which may have affected the interpretation of the results. Additionally, the overall survival (OS) data are not yet mature, and future final analyses may provide more information on the long-term efficacy of atezolizumab.

This study provides important clinical evidence for immunotherapy in ovarian cancer. Although the results did not meet expectations, it offers valuable references for future research directions and the optimization of treatment strategies.