Ana Oaknin, MD, PhD

“The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise, the probability of cure is quite low,” said European Society for Medical Oncology (ESMO) discussant of the PAOLA-1 trial, Ana Oaknin, MD, PhD, of the Vall d’Hebron Institute of Oncology, Barcelona. With this goal in mind, she added, “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.”

Building on Previous Clinical Trial Data

The findings build upon previous trials reported in 2011—GOG-218 and ICON-7—that established “global benefit” for the use of bevacizumab and led to a new front-line standard of care. Additionally, GOG-218 “broadened the knowledge” about ovarian cancer—confirming the prognostic impact of BRCA mutations on overall survival (but providing no evidence that BRCA mutation predicts bevacizumab activity alongside paclitaxel/carboplatin), she said.

The next advance came in 2018 with the phase IIII SOLO-1 trial, in which olaparib provided an “unprecedented” benefit in progression-free survival in patients with BRCA mutations (hazard ratio = 0.30; P < .001). This led to yet another new standard of care for this subset of patients with advanced ovarian cancer.

Thereafter, three additional trials solidified the benefit of poly (ADP ribose) polymerase (PARP) inhibitors as maintenance therapy in patients who achieve a response to chemotherapy. In this setting, olaparib, rucaparib, and niraparib received approval by European and U.S. regulatory agencies regardless of BRCA1/2 and homologous recombination deficiency (HRD) status.

“Chemotherapy-free regimens such as a combination of an antiangiogenic agent and a PARP inhibitor have emerged in platinum-sensitive recurrent ovarian cancer,” Dr. Oaknin commented. The phase III ovarian trials presented at this year’s ESMO Congress, she said, have identified a new population who significantly benefits: patients with HRD but not BRCA mutations.

Unanswered Questions

However, Dr. Oaknin raised several important questions about the findings of PAOLA-1: What is the contribution of bevacizumab, in the population with BRCA mutations, since the benefit was consistent with that observed in SOLO-1 with olaparib monotherapy? “The lack of an olaparib monotherapy arm is PAOLA-1’s weakness, making it difficult to determine whether the substantial progression-free survival benefit is due to the addition of olaparib or a synergistic effect of the combination. The latter does not seem to be supported by previous phase II studies,” she noted.

In addition, why did PAOLA-1 find no benefit for olaparib/bevacizumab in “the controversial” HRD-negative (ie, HRD-proficient) subgroup, whereas the PRIMA trial,¹ which she also discussed at this year’s ESMO Congress, did? It is possible that bevacizumab had a greater-than-anticipated effect, thus preventing olaparib from imparting additional benefits. PAOLA-1 also included patients whose HRD status was unknown, but Dr. Oaknin questioned whether the heterogeneity in this subset would be enough to account for this difference. She also suggested that the HRD-negative subset needs different stratification of the HRD score on the assay.

Finally, Dr. Oaknin brought up the issue of cost and potential toxicity with olaparib plus bevacizumab. “Adverse events in PAOLA-1 led to treatment discontinuation in 20%, the highest figure reported across PARP inhibitor trials, although there was no impact on quality of life,” she noted.

Ultimately, for the HRD-positive population (BRCA wild-type), olaparib plus bevacizumab led to a “robust” reduction in the risk of disease progression. According to Dr. Oaknin, this justifies giving this combination in the first-line setting to increase the potential for cure in these patients. “The longer the time without relapse,” Dr. Oaknin pointed out, “the better the chance to be a long-term responder or to be cured.” ■

DISCLOSURE: Dr. Oaknin has served as a consultant and on the speakers bureau for or received travel funding from AstraZeneca, Clovis Oncology, ImmunoGen, PharmaMar, Roche, and Tesaro.

REFERENCE

1. González-Martín A, Pothuri B, Vergote I, et al: Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). ESMO Congress 2019. Abstract LBA1. Presented September 28, 2019.