Final PFS2 analysis shows sustained PFS benefit of maintenance olaparib in ovarian cancer

The initial progression-free survival (PFS) improvement obtained with the addition of olaparib to bevacizumab was sustained beyond first progression, as reflected by the significant PFS2 benefit in women with newly diagnosed, advanced high‐grade ovarian cancer, according to the final PFS2 analysis of the phase III PAOLA-1*/ENGOT-ov25 trial.

In the primary analysis, adding olaparib to maintenance bevacizumab following first-line platinum-based chemotherapy led to a significant PFS benefit (median, 22.1 vs 16.6 months; hazard ratio [HR], 0.59; p<0.001). [NEJM 2019;381:2416-2428] “[This translated to] a 41-percent reduction in the risk of disease progression or death … However, PFS2 was immature [at the time],” said study co-investigator Dr Antonio Gonzalez Martin from the Clinica Universidad de Navarra, Madrid, Spain.

PAOLA-1/ENGOT-ov25 comprised 806 women with newly diagnosed, FIGO** stage III/IV serous endometrioid, ovarian, fallopian tube, and/or primary peritoneal cancer. Participants were randomized 2:1 to receive maintenance bevacizumab 15 mg/kg Q3W for 15 months, either in combination with olaparib 300 mg BID for up to 2 years (olaparib arm) or placebo (placebo arm).

In this final PFS2 analysis, after ~3 years of follow-up, a significant PFS2 benefit was seen in the olaparib vs the placebo arm in the intention-to-treat (ITT) cohort (median, 36.5 vs 32.6 months; HR, 0.78; p=0.0125). [ESMO 2020, abstract LBA33]

“The risk of second progression or death was reduced by 22 percent. It is worth noting that, following first progression, a PARP*** inhibitor was administered during first subsequent therapy to only 9 percent of women in the olaparib arm compared with 27 percent of women in the placebo arm,” Martin pointed out.

“[T]he interesting thing … is that [the curve] seemed to diverge after the 24-month period when olaparib was stopped, and … one can speculate why that may be,” commented discussant Dr Jonathan Ledermann from the University College London Cancer Institute, London, UK.

When stratified according to HRD^# status, PFS2 still favoured olaparib vs placebo in HRD-positive women including (median, 50.3 vs 35.3 months; HR, 0.56) and excluding tumour BRCA mutation (tBRCAm; median, 50.3 vs 30.1 months; HR, 0.60).

The PFS2 benefit was supported by a significant TSST^## benefit in favour of olaparib vs placebo, both in the ITT cohort (median, 38.2 vs 31.5 months; HR, 0.78; p=0.0115) and on subgroup analyses (HR, 0.48 for both HRD-positive women and women with tBRCAm).

Despite the higher discontinuation rate with olaparib vs placebo due to adverse events (AEs; 21 percent vs 6 percent), no new safety signals were observed. The findings were consistent with that observed in the primary PFS analysis, noted Martin.

Also, regarding AEs of special interest, the rates of MDS/AML/AA^### were similar between the olaparib and the placebo arms despite longer follow-ups (1.1 percent vs 1.5 percent), as were the rates of new primary malignancies (2.6 percent vs 1.9 percent) and pneumonitis/interstitial lung disease/bronchitis (1.1 vs 0 percent).

Importantly, no new cases of MDS/AML/AA were reported in the olaparib arm during the final PFS2 analysis. Of the four cases in the placebo arm, three received a PARP inhibitor as first subsequent therapy before AML onset, noted Martin.

Interim overall survival (OS) analysis was immature owing to the low event rate (38 percent). “[As such,] definitive conclusions cannot be drawn … Updated OS data will be presented at greater maturity,” said Martin.

“[L]onger-term analysis and secondary endpoint evaluation suggest that OS benefits will occur. OS data will also help disentangle further the benefits of first- vs second-line use of PARP inhibitors, particularly in the [tBRCAm] and BRCA-wild-type/HRD populations,” said Ledermann.

“[Together with findings from the SOLO1 trial, these are] interesting data that is reshaping the treatment of ovarian cancer and providing hitherto unseen benefits to women with this disease,” added Ledermann.