The phase III PAOLA-1/ENGOT-ov25 trial evaluated the addition of maintenance olaparib to bevacizumab in women with advanced ovarian cancer who were in response after first-line platinum-based CTx with bevacizumab.


In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant progression-free survival (PFS) benefit, particularly in homologous recombination deficiency (HRD)-positive pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al.NEJM 2019). Researchers explored efficacy in HRD+ pts by disease stage and presented data.

In a poster session during the 2021 ASCO Annual Meeting on the PFS and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.  Results showed that at a median follow-up of 24.8 months, the median PFS was 39.3 months (95% CI, 36.0–not evaluable [NE]) with olaparib/bevacizumab in patients with HRD-positive tumors and stage III disease vs 19.9 months (95% CI, 17.7-23.4) with bevacizumab alone (HR, 0.32; 95% CI, 0.22-0.47).

Patients with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy bevacizumab received bevacizumab (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage.

Patients enrolled to the study had newly diagnosed, FIGO stage III to stage IV high-grade serous or endometroid ovarian, fallopian tube, and/or peritoneal cancer. Patients received first-line treatment with up-front or interval surgery, platinum/taxane-based chemotherapy, and two or more cycles of bevacizumab. Study participants were randomized to receive either olaparib at 300 mg twice daily for 2 years plus bevacizumab, or placebo plus bevacizumab. Of the 806 patients who were randomized on study, 48% (n = 387) had HRD-positive status; 70% (n = 272) had stage III disease, and 30% (n = 115) had stage IV disease.

Additional data showed that in those with HRD positivity and stage III disease, The 2-year PFS rate with olaparib/bevacizumab was 72% vs 36% with bevacizumab alone. In those with HRD positivity and stage IV disease, the 2-year PFS rates in the investigative and control arms were 52% and 17%, respectively. In patients with HRD-positive tumors and stage IV disease, the median PFS with the combination was 25.1 months (95% CI, 22.0-37.2) vs 12.8 months (95% CI, 10.4-15.8) with bevacizumab alone (HR, 0.32; 95% CI, 0.20-0.52). Moreover, in patients with lower risk disease, defined as those with stage III disease who did not have residual disease following up-front surgery, the median PFS2 was not reached with the doublet vs 44.3 months (95% CI, 37.9–NE) with bevacizumab alone.

In those with higher risk disease, defined as those with stage III disease who have residual disease following up-front surgery or who received neoadjuvant chemotherapy or those who have stage IV disease, the median PFS2 with the combination was 50.3 months (95% CI, 34.6-50.3) vs 32.6 months (95% CI, 25.7-42.2) with bevacizumab alone (HR, 0.66; 95% CI, 0.47-0.93).

“Remarkably, the 2- and 3-year PFS2 rates were greater than 90% with maintenance olaparib plus bevacizumab in lower risk patients with HRD-positive tumors who benefitted from complete resection during up-front surgery,”  says Patricia Pautier, MD, lead study author and head of the Medical Day Hospital Unit at the Institut Gustave Roussy Cancer Campus, said during a poster presentation on the data.

As first-line maintenance treatment of patients with HRD-positive, advanced high-​grade ovarian cancer, the addition of olaparib to bevacizumab in the fresulted in a significant improvement in PFS, especially in those with HRD positivity, including those with BRCA mutations (HR, 0.33; 95% CI, 0.25-0.45). In this subgroup of patients, the median PFS was 37.2 months and 17.7 months in the investigative and control arms, respectively. In those with HRD-positive tumors without BRCA mutations, the median PFS was 28.1 months and 16.6 months in the investigative and control arms, respectively (HR, 0.43; 95% CI, 0.28-0.66).2

These data supported the May 2020 FDA approval of olaparib plus bevacizumab for maintenance treatment.

 

Reference: Pautier P, Harter P, Pisano C, et al. Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial. J Clin Oncol. 2021;39(suppl 15)5514. doi:10.1200/JCO.2021.39.15_suppl.5514