PAOLA-1 Shows Benefit from Olaparib After Bevacizumab in Ovarian Cancer

Paul D. DiSilvestro, MD

Director, Program in Women’s Oncology

Women & Infants Hospital of Rhode Island and Care New England Health System

Division director, Gynecologic Oncology

Department of Obstetrics and Gynecology

Warren Alpert Medical School of Brown University

Providence, RI

(Read Part 1 here)

(Read Part 2 here)

Targeted OncologyTM: What did the PAOLA-1 trial (NCT02477644) show about PARP inhibitor maintenance?

DISILVESTRO: This was a trial randomly assigning patients who had received bevacizumab [Avastin] during primary therapy, [to] either olaparib [Lynparza] or placebo. The addition of olaparib or placebo was for 24 months. The primary outcome variable was PFS [progression-free survival] from the time of randomization with some other secondary end points. The nuance is that bevacizumab was technically only required to have been administered in 2 cycles prior to randomization.

If we look at the patient characteristics, there was a fair proportion with stage IV disease.¹ A lot of patients that were on this trial were treated in Europe, where there is an indication for the use of bevacizumab in high-risk patients, so you have a population where this would have been utilized. Other baseline characteristics were well balanced between the arms.

If we look at the PFS outcome overall in the intention-to-treat population, the hazard ratio for progression or deaths was 0.59 favoring olaparib versus placebo in addition to bevacizumab.¹

[These data show why we are] only doing this in HRD [homologous recombination deficiency]-positive patients. For HRD-positive patients who had tumor BRCA mutations, the hazard ratio for PFS is 0.33. For those who are HRD positive but did not have tumor BRCA mutations, the hazard ratio was 0.43. And, if they were homologous recombination proficient [HRP] or HRD status unknown, the HR was 0.92, not statistically significant. That was the rationale behind why this is indicated only in HRD patients as frontline maintenance. But you had to have already started the patient on bevacizumab and…there are many practitioners that don’t necessarily utilize bevacizumab in the frontline setting.

If we look at the different subgroup analyses, [the confidence interval for] tumor HRD status of negative or negative or unknown crosses 1.00, meaning it was not significant. Otherwise, in terms of the BRCA mutation status and HRD, those remain significant.

What recent analyses were presented for this trial?

There was a presentation at 2022 European Society for Medical Oncology Annual Meeting looking at the OS data for the PAOLA-1 trial.² The median OS for the BRCA-mutated patients was 75.2 months in the combination arm versus [66.9] months in the placebo arm, yielding a hazard ratio of 0.60 [95% CI, 0.39-0.93]. If you look at the HRD-positive patients excluding BRCA mutated, you had a not-yet-reached median OS versus 52.0 months and a hazard ratio of 0.71, but [the upper bound of the confidence interval] crosses 1.00 [95% CI, 0.45-1.13]. In the HRP group, there was no benefit in the olaparib arm versus placebo; that [points] towards the fact that BRCA mutation as a prognostic variable suggests an OS benefit that’s significant. We did not see the significance in the HRD [group] that was not BRCA mutated.

Adverse events were common to what we [expect].¹ If bevacizumab is in the mix, we have the additional toxicities of hypertension and proteinuria, which are common in the use of bevacizumab. Overall, in the combination arm, they had a 20% discontinuation rate based on toxicity versus 6% in the placebo arm with bevacizumab.

_References:

_{1. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{2. Ray-Coquard I, Leary A, Pignata S, et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Ann Oncol. 2022;33 (suppl_7):S808-S869. doi:10.1016/annonc/annonc1089}