FDA Approves Maintenance Olaparib/Bevacizumab in Advanced Ovarian Cancer

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The FDA granted approval to the combination of olaparib and bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab and whose cancer is associated with homologous recombination deficiency–positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.

The FDA granted approval to the combination of olaparib (Lynparza) and bevacizumab (Avastin) for the maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response (PR) to first-line platinum-based chemotherapy with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD)–positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability, according to an email communication from the American Association of Cancer Research.1

“This new regimen demonstrated the longest median progression-free survival ever reached before in this population of ovarian cancer not restricted to BRCA mutation and this approval will change clinical practice in how women with advanced ovarian cancer are treated in the first-line maintenance setting. This combination in the first-line setting could increase the potential for cure in these patients because the longer the time without relapse, the better the chance to be a long-term responder or to be cured,” Isabelle Ray-Coquard, MD, PhD, the primary investigator of the PAOLA-1/ENGOT-ov25 trial, told Targeted Oncology.

The combination was approved based on data from the phase III PAOLA-1/ENGOT-ov25 trial, which were presented during the 2020 Society for Gynecologic Oncology (SGO) Virtual Annual Meeting I, showing a 41% improvement in the risk of progression or death with the combination compared with bevacizumab alone.2

The PAOLA-1/ENGOTov25 trial was the first phase III trial to evaluate the efficacy and safety of maintenance therapy with a PARP inhibitor in patients with advanced ovarian cancer who are receiving first-line standard-of-care therapy, regardless of their BRCA mutation status.

“The goal of first line, including maintenance, treatment for women with newly diagnosed advanced ovarian cancer is to delay relapse. Unfortunately, the risk of relapsing is high, as 2 out of 3 women relapse within 3 years of initial diagnosis. PAOLA-1 met its primary objective, demonstrating a statistically significant and clinical meaningful improvement in progression-free survival when olaparib was added to first-line standard-of-care bevacizumab maintenance treatment in the majority of [patients with] advanced ovarian cancer, as the patient selection was not restricted by surgical outcome,” explained Ray-Coquard, a medical oncologist in the Medical Oncology Department and the Institute for Clinical Science at the Centre Leon Berard in Lyon, France.

The median progression-free survival (PFS) in the intention-to-treat population, the study’s primary end point, was 22.1 months with the olaparib and bevacizumab combination regimen versus 16.6 months observed with bevacizumab and placebo (HR, 0.59; 95% CI, 0.49-0.72; P <.0001), by investigator assessment. The median duration of follow-up was 22.7 months in the combination arm and 24.0 months in the bevacizumab arm.

By blinded independent central review, the median PFS was 26.1 months with the combination compared with 18.3 months with bevacizumab and placebo (HR, 0.63; 95% CI, 0.51-0.77; P <.0001).

A total of 806 patients were randomized. In the combination arm, there were 535 patients, and in the monotherapy group, 267 patients were included. A total of 474 out of 806 patients were evaluated for PFS.

Results previously published in the New England Journal of Medicine in late 2019, showed that in the primary analysis, the median follow-up was 22.7 months (range, 18.0-27.7) in the olaparib/bevacizumab arm versus 24.0 months (range, 18.7-27.7) in the monotherapy arm, which resulted in a median duration of follow-up of 22.9 months for the combined groups. The investigator-assessed PFS observed in the combination arm was 22.1 months versus 16.6 months observed with bevacizumab and placebo (HR, 0.59; 95% CI, 0.49-0.72; P <.001).3

Across multiple subgroups of patients with advanced ovarian cancer, the combination of olaparib and bevacizumab maintained its superiority to bevacizumab and placebo in terms of PFS.

For patients with BRCA-mutant tumors, the median PFS was 37.2 months with the addition of olaparib to bevacizumab compared with 21.7 months in the bevacizumab monotherapy group (HR, 0.31; 95% CI, 0.20-0.47). Among those without BRCA mutations, the median PFS was 18.9 months with the combination versus 16.0 months with monotherapy (HR, 0.71; 95% CI, 0.58-0.88).

In a subgroup of participants with homologous recombination deficiency (HRD)–positive tumors, as defined by having a tumor score ≥42 on the myChoice HRD Plus assay, the median PFS observed was 37.2 months in the combination arm compared with 17.7 months in the monotherapy arm (HR, 0.33; 95% CI, 0.25-0.45). Of the patients with HRD-positive tumors, those who did not have a BRCA mutation demonstrated a median PFS of 28.1 months with olaparib/bevacizumab versus 16.6 months with bevacizumab/placebo (HR, 0.43; 95% CI, 0.28-0.66).

The median PFS was lower in both arms among patients with HRD-negative tumors or whose HRD status was unknown (n = 419). Specifically, those who received combination therapy had a median PFS of 16.9 months compared with 16.0 months in those who received monotherapy (HR, 0.92; 95% CI, 0.72-1.17). In the remaining patients with HRD-negative tumors (n = 277), the median PFS was 16.6 months with the addition of olaparib versus 16.2 without (HR, 1.00; 95% CI, 0.75-1.35).

The median time until the first subsequent treatment in the combination and monotherapy arm respectively was 24.8 versus 18.5 months (HR, 0.59; 95% CI, 0.49-0.71). At the time of data cutoff, the interim analysis data for PFS2 were immature, but showed an 18-month rate of freedom from second disease progression of 79% in the combination arm versus 80% in the monotherapy arm (HR, 0.86; 95% CI, 0.69-1.09).

In terms of safety, the most common all-grade adverse events (AEs) that occurred at a higher incidence in patients who received olaparib plus bevacizumab versus bevacizumab alone were fatigue (53% vs 32%, respectively), nausea (53% vs 22%), and anemia (41% vs 10%). The most common any-grade AE that occurred at a higher incidence in the monotherapy group than the combination group was hypertension (60% vs 46%, respectively).

Overall, 31% of patients experienced a serious AE. Serious anemia occurred at a higher incidence in the olaparib/bevacizumab group than the placebo/bevacizumab group (6% vs 1%). Serious hypertension occurred at a higher incidence in the placebo/bevacizumab group than the olaparib/bevacizumab group (13% vs 9%). Approximately 1% of patients in each arm experienced fatal AEs.

A portion of patients developed a secondary disease, including myelodysplastic syndromes, acute myeloid leukemia, or aplastic anemia, during the study. Of these patients, 1% were from the combination group and the other 1% were from the monotherapy group. Additionally, about 1% of patients in each group developed a new primary cancer.

Six patients in the olaparib plus bevacizumab group experienced pneumonitis, interstitial lung disease, or bronchiolitis, but no patients in the placebo group experienced these toxicities.

Most of the AEs were managed by dose modification rather than treatment discontinuation. However, nausea and anemia were the most common AEs that did lead to treatment discontinuation.

The AEs notable as special interest for treatment with bevacizumab across all grades in the combination and monotherapy groups, respectively, were most commonly hypertension (46%, 50%), proteinuria (6%, 15%), and tooth abscess (3%, 1%). There were few grade ≥3 AEs of special interest for bevacizumab.

A health-related quality of life assessment was conducted in this study but showed no clinical significance in either group. The estimated global health status quality-of-life score difference between the olaparib plus bevacizumab group versus the placebo plus bevacizumab group was 1.56 points (95% CI, –0.42 to 3.55), which was not considered clinically significant.

Patients in the randomized, double-blind, placebo-controlled PAOLA-1 trial were randomized 2:1 to receive olaparib 300 mg twice daily or placebo for at least 3 weeks with a limit of 9 weeks following the last dose of chemotherapy. Treatment continued for 24 months from randomization or until the occurrence of disease progression, or unacceptable toxicity, whichever came first. The study did not allow crossover between arms. Patients who progressed in either study group were then treated with other agents based on investigator choice.

Bevacizumab was added to either arm at 15 mg/kg of body weight, administered every 3 weeks for up to 15 months.

The primary end point of the study was PFS. The secondary end point included PFS2, overall survival, and safety and tolerability.

Patients aged 18 years or older with a diagnosis of advanced high-grade serous or endometrial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer were included in the study. Participants were required to have an ECOG performance status of 0 or 1, and a tumor sample for central testing of BRCA mutation status.

The investigators noted one minor limitation to the trial, which did not affect the positivity of the results: “The lack of a maintenance olaparib monotherapy comparator group is a limitation of the PAOLA-1 trial, making it difficult to conclude whether the progression-free survival benefit seen in patients with HRD-positive tumors without BRCA mutations (who were not included in the SOLO1 trial) was due largely to the addition of olaparib or whether a synergistic effect occurred with olaparib and bevacizumab,” wrote Ray-Coquard et al in the published report.

Overall the study was positive for the combination of olaparib and bevacizumab, showing PFS benefit across all evaluated subgroups.

References

1. FDA Approves Olaparib Plus Bevacizumab as Maintenance Treatment for Ovarian, Fallopian Tube, or Primary Peritoneal Cancers. AACR. Published May 8, 2020. Accessed May 8, 2020.

2. Ray-Coquard I. Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care. Presented at: 2020 Society for Gynecologic Virtual Annual Meeting I.

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