Maintenance olaparib confers survival benefit for HRD+ ovarian cancer patients

In the final overall survival (OS) analysis of the phase III PAOLA-1*/ENGOT-ov25 trial, the addition of olaparib to bevacizumab provided a survival benefit for women with newly diagnosed advanced ovarian cancer with HRD**-positive (HRD+) tumours.

“[In] this final analysis, [we] investigated whether the progression-free survival (PFS) benefit observed in the primary analysis translates to an OS advantage at 5 years in the first-line setting,” said Dr Shoji Nagao from the Okayama University Hospital, Okayama, Japan, at ESMO Asia 2022.

“[Although half] of the patients in the control arm received a PARP*** inhibitor post-progression as subsequent therapy, [our findings showed that] the addition of maintenance olaparib to bevacizumab provided a clinically meaningful OS benefit in patients who were HRD+ regardless of BRCA mutation status,” Nagao continued.

The 806 participants were randomized 2:1 to receive maintenance bevacizumab 15 mg/kg Q3W for 15 months, combined with olaparib 300 mg BID for up to 2 years (olaparib arm) or placebo (control arm). About 30 percent of the overall cohort had stage IV disease and half had upfront surgery. Of those who received surgery, ~40 percent had residual disease. [ESMO Asia 2022, abstract 176O]

In the HRD+ subgroup, after a median OS follow-up of >5 years, there was a 38-percent reduction in the risk of death (hazard ratio [HR], 0.62) and 5-year OS rate was higher in the olaparib vs the control arm (66 percent vs 48 percent). Despite the longer median OS with olaparib vs placebo (75.2 vs 57.3 months), Nagao noted that the data on olaparib is unstable due to raw data maturity in this arm and could have been an underestimation.

The OS benefit in this subgroup remained, particularly among those with BRCA mutation (73 percent vs 54 percent; HR, 0.60) and those who were HRD+ but excluding those with BRCA mutation (55 percent vs 44 percent; HR, 0.71).

This benefit was not seen in the intention-to-treat cohort (median 56.5 vs 51.6 months; HR, 0.92) and among those who were HRD-negative (26 percent vs 32 percent; HR, 1.19).

Updated PFS, AESIs

“The OS advantage observed in the HRD+ population was supported by the updated PFS analysis showing that the addition of maintenance olaparib to bevacizumab provided a 59-percent reduction in the risk of disease progression or death compared with bevacizumab alone (HR, 0.41),” said Nagao.

Median PFS was markedly longer (46.8 vs 17.6 months) and the fraction of women who had not relapsed after 5 years was more than twice as high in the olaparib vs the control arm (46 percent vs 19 percent). “[These data suggest that olaparib-bevacizumab] may have the potential to cure more than twice as many newly diagnosed HRD+ patients,” Nagao continued.

All patients have discontinued treatment at the final PFS2 analysis but monitoring for AESIs^# ran until the final OS analysis. With longer follow-up, the rates of MDS/AML/AA^## (1.7 percent vs 2.2 percent) and the incidence of new primary malignancies^### (4 percent vs 3 percent) remained balanced between the olaparib and the control arms.

Soc for HRD+ patients

“In ovarian cancer trials in the first-line setting, OS improvement has been difficult to demonstrate because of the long post-progression survival period [wherein] patients typically receive several lines of post-progression therapy,” Nagao explained.

“[Our current] data confirm the addition of olaparib to bevacizumab as standard of care for HRD+ patients in this setting, and the importance of precision medicine and biomarker testing to guide treatment decisions,” he concluded.