Olaparib Plus Bevacizumab Extends PFS as Frontline Maintenance in Ovarian Cancer

Isabelle Ray-Coquard, MD, PhD

The combination of olaparib (Lynparza) and bevacizumab (Avastin) as frontline maintenance improved the median progression-free survival (PFS) by 5.5 months over bevacizumab and placebo in patients with newly diagnosed, advanced ovarian cancer following prior treatment with a platinum-based chemotherapy plus bevacizumab, according to the phase III PAOLA-1 findings presented at the 2019 ESMO Congress.¹

Median PFS in the olaparib arm was 22.1 months versus 16.6 months in the placebo arm, representing a 41% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.59; 95% CI, 0.49-0.72;P<.0001). This benefit was observed across all patient subsets but was more pronounced for those with tumors testing positive forBRCA1/2mutations (tBRCAm) and for those with a homologous recombination deficiency (HRD) score of &ge;42 by the myChoice HRD Plus assay (HRD-positive).

&ldquo;PAOLA-1 met its primary objective, demonstrating a statistically significant improvement in PFS in the intent-to-treat population when olaparib, compared with placebo, was added to first-line standard-of-care bevacizumab maintenance treatment,&rdquo; said study author Isabelle Ray-Coquard, MD, PhD, from the Centre Leon B&eacute;rard, Universit&eacute; Claude Bernard, in Lyon, France. &ldquo;This was the first randomized trial to explore the efficacy and the safety of the combination of olaparib and bevacizumab in patients with newly diagnosed ovarian cancer.&rdquo;

The PAOLA-1 trial randomized patients to receive bevacizumab at 15 mg/kg every 3 weeks on day 1 with olaparib tablets at 300 mg twice daily (n = 537) or matched placebo (n = 269). All patients had newly diagnosed FIGO stage III or IV high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer. Patients were enrolled regardless of the type or extent of surgery (upfront or interval). All patients had received prior platinum-based chemotherapy and bevacizumab for &ge;3 cycles and had no evidence of disease, a complete response, or a partial response upon enrollment.

There was a median of 6 weeks from the last cycle of chemotherapy to randomization in the study, Ray-Coquard noted. &ldquo;It is an important point to consider when comparing the results to other data,&rdquo; she said. The median time from first cycle of chemotherapy to randomization was 7 months.

&ldquo;Patient selection was not restricted by surgical outcome orBRCAmutation status, so participants represent the general population of women with advanced ovarian cancer,&rdquo; Ray-Coquard said. &ldquo;Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors and today&rsquo;s results appear to support this. In addition, olaparib did not increase side effects compared to placebo.&rdquo;

In the tBRCAm subgroup, the median PFS was 37.2 months with olaparib and bevacizumab compared with 21.7 months for placebo and bevacizumab (HR, 0.31; 95% CI, 0.20-0.47). The 24-month PFS rate was 76% in the olaparib group versus 39% for placebo. In the HRD-positive group, which included those with tBRCAm, the median PFS was 37.2 months compared with 17.7 months (HR, 0.33; 95% CI, 0.25-0.45). In HRD-positive patients who did not have aBRCAmutation, the median PFS was 28.1 months with olaparib and 16.6 months with placebo (HR, 0.43; 95% CI, 0.28-0.66).

&ldquo;Prespecified subgroup analyses showed that patients with tumorBRCAmutations and patients with a positive HRD status had the greatest PFS benefits,&rdquo; said Ray-Coquard. &ldquo;The results reveal a patient population beyond tBRCAm patients, who are HRD-positive, that experiences substantial benefit from maintenance treatment with olaparib and bevacizumab.&rdquo;

There were more grade &ge;3 adverse events (AEs) in the olaparib arm compared with the placebo group; however, there was no a clinically meaningful difference in health-related quality of life between the arms. Dose interruptions were required for 54% of those in the olaparib group compared with 24% in the placebo arm. Dose reductions were required for 41% and 7% of patients and dose discontinuations were needed for 20% and 6% of patients, in the olaparib and placebo groups, respectively.

The most common grade &ge;3 AEs in the olaparib group and placebo arms, respectively, were hypertension (19% vs 30%) and anemia (17% vs <1%). There were 4 treatment-emergent deaths in the placebo group and 1 in the olaparib arm.

&ldquo;The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low,&rdquo; ESMO discussant Ana Oaknin, MD, PhD, from the Vall d&acute;Hebron Institute of Oncology, said in a statement. Based on this goal, she added that &ldquo;the combination of bevacizumab and olaparib as maintenance therapy should become a new standard of care for patients with advanced ovarian cancer...this trial is a significant step forward in treatment for these women.&rdquo;

In December 2018, the FDA approved olaparib monotherapy as a frontline maintenance treatment for patients with deleterious or suspected deleterious germline or somaticBRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.

This approval was based on findings from the phase III SOLO-1 trial,²in which olaparib monotherapy reduced the risk of disease progression or death by 70% compared with placebo in patients withBRCA-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41;P<.0001). The median PFS had not yet been reached in the olaparib arm and was 13.8 months with placebo.

Comparing the SOLO-1 results to the PAOLA-1 findings, Ray-Coquard noted that &ldquo;inBRCA-mutated patients, the HR is 0.31 in favor of the combination of olaparib and bevacizumab [in PAOLA-1]. This is similar to what we observed in the SOLO-1 trial, where olaparib monotherapy was compared with placebo. The PFS in the control arm is longer in PAOLA-1 than the SOLO-1 trial, which is due to the use of bevacizumab.&rdquo;

References:

1. Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA2_PR.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Eng J Med. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.