PAOLA-1 at 5 years: Maintenance olaparib + bevacizumab support long-term remission in HRD-positive ovarian cancer

Post hoc analysis of the phase III PAOLA-1/ENGOT-ov25 trial reports respective 5-year progression-free survival (PFS) rates of 72 percent vs 28 percent and 5-year overall survival (OS) rates of 88 percent vs 61 percent for maintenance olaparib plus bevacizumab vs bevacizumab alone in lower-risk homologous recombination deficiency (HRD)–positive patients with newly diagnosed advanced ovarian cancer.

PAOLA-1’s 2-year follow-up showed that combination therapy with maintenance olaparib plus bevacizumab provided a PFS benefit in patients with newly diagnosed advanced ovarian cancer whose tumours tested positive for HRD, irrespective of clinical risk. [N Engl J Med 2019;381:2416-2428] A clinically meaningful improvement in OS was subsequently shown at 5 years in the HRD-positive subgroup. [Ann Oncol 2023;34:681-692] The present post hoc analysis reports updated PFS results at 5 years and final OS results classified by clinical risk and HRD status. [Int J Gynecol Cancer 2024;34:550-558]

Of 806 patients randomized to receive olaparib plus bevacizumab (n=537) or placebo plus bevacizumab (n=269), 74 percent were at higher risk and 26 percent were at lower risk of disease progression. Higher-risk patients either had stage III disease, underwent upfront surgery and had residual disease or had received neoadjuvant chemotherapy or had stage IV disease. Lower-risk patients had stage III disease, underwent upfront surgery and had complete resection.

In higher-risk HRD-positive patients, median 5-year PFS was 31.3 months with olaparib plus bevacizumab and 15.9 months with placebo plus bevacizumab (hazard ratio [HR], 0.46; 95 percent confidence interval [CI], 0.34–0.61). Respective estimated 5-year PFS rates were 35 percent vs 15 percent.

In lower-risk HRD-positive patients, median PFS was unstable in the olaparib group due to lack of events vs 22.3 months in the placebo group (HR, 0.26; 95 percent CI, 0.15–0.45), while estimated 5-year PFS rates were 72 percent vs 28 percent, respectively.

Median OS in higher-risk HRD-positive patients was unstable in the olaparib group due to lack of events vs 54.0 months with placebo (HR, 0.70; 95 percent CI, 0.50–1.00). Estimated 5-year OS rates were 55 percent vs 42 percent, respectively.

While median OS was not reached in either treatment group in lower-risk HRD-positive patients, addition of olaparib maintenance to bevacizumab reduced risk of death by 69 percent vs placebo (HR, 0.31; 95 percent CI, 0.14–0.66). Estimated of 5-year OS rates were 88 percent vs 61 percent for olaparib vs placebo.

“OS analyses were unadjusted for subsequent poly[ADP-ribose] polymerase [PARP] inhibitor therapy, yet olaparib produced an OS benefit in the HRD-positive subgroup, despite 56 percent of higher-risk patients and 40 percent of lower-risk patients in the placebo group receiving subsequent PARP inhibitor therapy [vs 19 percent and 14 percent of patients in the olaparib group],” pointed out the investigators.

The incidence of myelodysplastic syndrome, acute myeloid leukaemia, or aplastic anaemia was balanced between treatment arms in both higher-risk and lower-risk patients, including those with HRD-positive disease.

“Results of this post hoc analysis indicate that maintenance olaparib plus bevacizumab should be considered one of the standards of care for all patients with newly diagnosed advanced HRD-positive ovarian cancer, regardless of whether they are considered at higher or lower risk of disease progression. PFS rates at 5 years support long-term remission and suggest an increased potential for cure with the addition of olaparib to platinum-based chemotherapy plus bevacizumab, with particular benefit suggested in lower-risk patients,” summarized the investigators.