Bevacizumab With Olaparib Extends Time to Toxicity in Patients With Newly Diagnosed Ovarian Cancer

Florence Joly, MD, PhD

The addition of olaparib (Lynparza) to bevacizumab (Avastin) significantly delayed the onset of treatment-related toxicities in patients with newly diagnosed, advanced ovarian cancer, compared with placebo, according to a subanalysis of the phase 3 PAOLA-1/ENGOT-ov25 trial (NCT02477644). Findings were presented during the 2022 Annual ASCO meeting.

In the intention-to-treat population, the median duration of time without symptoms or toxicity for all adverse events (AEs) grade 2 or greater was 14.1 months (95% CI, 12.5-16.1) in the bevacizumab/olaparib arm and 7.7 months (95% CI, 5.9-9.1) in the placebo arm. The median onset for grade 2 or higher toxicities with symptoms was 17.2 months (95% CI, 16.0-20.1) vs 11.3 months (95% CI, 9.7-13.6), respectively.

Moreover, among patients who experienced grade 2 or higher AEs directly related to olaparib, the median duration was 21.9 months (95% CI, 20.2-22.5) vs 16.6 months (95% CI, 14.6-18.0), respectively.

“The substantial progression-free survival [PFS] benefit provided by maintenance olaparib plus bevacizumab was supported by significant TWiST [time without symptoms or toxicity] benefits—almost twice the median duration [compared with the control group],” Florence Joly, MD, PhD, Centre François Baclesse, said in a presentation of the findings. “Notably, in the HRD [homologous recombination deficiency]-positive group, [there was] almost triple the median TWiST.”

PAOLA enrolled individuals with newly diagnosed stage II-IV, high-grade, serious, or endometroid ovarian, fallopian tube and/or primary peritoneal cancer following frontline treatment with platinum-taxane based chemotherapy plus 2 or more cycles of bevacizumab and upfront or interval debulking surgery. Patients were randomly assigned 2:2 to receive either olaparib tablets at 300 mg twice daily or placebo for at least 2 years, in addition to bevacizumab, as maintenance therapy.

Previously reported findings showed that maintenance olaparib plus bevacizumab yielded superior PFS compared with bevacizumab plus placebo, following frontline treatment with platinum-based chemotherapy and bevacizumab. Of note, patients who tested positive for HRD (BRCA1 and/or BRCA2 mutation and a genomic instability) had a pronounced benefit from the drug combination, and experienced a median PFS of 37.2 months, compared with 17.7 months compared with bevacizumab and placebo.

At the 2022 ASCO meeting, investigators reported on safety, the trials’ secondary end point. Specifically, the TWiST analysis captured outcomes between randomization and disease progression. Patients were stratified by HRD status, and 3 different approaches were used to understand significant toxicities within the trial: investigators reported on all grade 2 or higher AEs, all grade 2 or higher AEs with symptoms, and all grade 2 or higher AEs selected to be linked with olaparib (ie, fatigue, nausea, vomiting, and anemia).

In the subset of patients with HRD-positive disease, the median duration of time without symptoms or toxicity for all AEs grade 2 or greater was 24.4 months (95% CI, 19.3-not estimable [NE]) in the olaparib arm and 7.4 months (95% CI, 5.8-11.2) in the placebo arm (P < .0001). For grade 2 or greater toxicities with symptoms, the median duration was 36.6 months (95% CI, 22.4-NE) vs 12.6 months (95% CI, 9.8-15.6), respectively (P < .0001). For severe AEs directly related to olaparib, the median duration was 36.6 months (95% CI, 31.9-NE) vs 17.4 months (95% CI, 15.1-19.4), respectively (P < .0001).

Among patients whose HRD status was negative or unknown, the median duration of time without symptoms or toxicity for all AEs grade 2 or greater was 8.5 months (95% CI, 6.8-11.4) in the olaparib arm and 7.7 months (95% CI, 5.9-9.1) in the placebo arm (P = .1840). For grade 2 or greater toxicities with symptoms, the median duration was 11.5 months (95% CI, 10.0-14.9) vs 10.5 months (95% CI, 8.5-14.0), respectively (P = .3772).

Moreover, among HRD negative patients who experienced grade 2 or higher AEs directly related to olaparib, the median duration was 16.6 months (95% CI, 14.9-18.0) vs 15.6 months (95% CI, 13.8-18.1), respectively (P = .8021).

Reference

Joly F, Chabaud S, Cropet C, et al. Time without symptoms or toxicity (TWiST) in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib or placebo plus bevacizumab: analysis of PAOLA-1/ENGOT-ov25 phase III trial. J. Clin. Oncol. 2022;40(suppl 16):5562. doi:10.1200/JCO.2022.40.16_suppl.5562