Proponents of combining bevacizumab with poly (ADP-ribose) polymerase (PARP) inhibition to treat advanced ovarian cancer now have more data to support the maintenance regimen, according to an updated analysis of the phase III PAOLA-1 trial presented during the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer Webinar Series.¹

In women with newly diagnosed ovarian cancer, front-line maintenance therapy with olaparib plus bevacizumab improved progression-free survival regardless of the timing of surgery or residual disease status after surgery vs bevacizumab alone. However, the magnitude of the benefit of the combination therapy was greatest when surgery achieved complete debulking in the upfront setting (hazard ratio [HR] = 0.47), authors of the study reported.

Christoph Grimm, MD

“When primary debulking surgery achieved no residual disease, olaparib plus bevacizumab maintenance resulted in an additional 17.2 months of median progression-free survival vs bevacizumab alone,” said gynecologic oncologist Christoph Grimm, MD, Associate Professor and Senior Physician at the Medical University of Vienna, Austria. “These results show that gynecologic oncologists are critical for hybrid ovarian cancer management to achieve complete surgical resection and optimize maintenance therapy with olaparib plus bevacizumab.”

PAOLA-1: Primary Endpoint Met

In an encore presentation of the PAOLA-1 trial, first reported at the European Society for Medical Oncology (ESMO) 2019 Congress,² Isabelle Ray-Coquard, MD, PhD, noted the phase III study evaluated olaparib plus bevacizumab maintenance in 806 patients who responded to first-line platinum-based chemotherapy plus bevacizumab. This trial included a broad, front-line population that was not restricted by surgical outcome or BRCA mutation status.

“PAOLA-1 met its primary objective, demonstrating a statistically significant improvement in progression-free survival in the intention-to-treat population when olaparib compared with placebo was added to first-line standard-of-care bevacizumab maintenance treatment,” said Dr. Ray-Coquard, of the Centre Leon Berard, Claude Bernard, and Professor in Medical Oncology, Claude Bernard University Lyon, France.

In addition, prespecified subgroup analyses showed that patients with BRCA-mutated tumors and patients with a positive homologous recombination–deficiency (HRD) status had the greatest progression-free survival benefits. “The results reveal that a patient population beyond those with tumor BRCA-mutated disease who are HRD positive may experience substantial benefit from maintenance treatment with olaparib and bevacizumab,” noted Dr. Ray-Coquard. “Of note, the addition of olaparib did not affect bevacizumab tolerability or health-related quality of life.”

“The addition of olaparib did not affect bevacizumab tolerability or health-related quality of life.”

— Isabelle Ray-Coquard, MD, PhD

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Efficacy by Timing of Surgery and Residual Disease Status

During the SGO webinar, Dr. Grimm presented an updated analysis of PAOLA-1 that evaluated the efficacy of maintenance olaparib plus bevacizumab by the timing of surgery and the presence of residual tumor after surgery.³ As Dr. Grimm reported, the PAOLA-1 trial population was unselected by biomarker status or surgery outcome, meaning it is “representative of most patients in clinical practice.” Prespecified analysis evaluated progression-free survival by the timing of surgery (upfront or interval), and post-hoc analysis evaluated progression-free survival by the timing of surgery combined with residual disease status after surgery.

Treatment groups were well balanced with respect to the type of surgery, residual tumor status, and biomarker status, added Dr. Grimm.

Analysis of progression-free survival by the timing of surgery showed a significant difference between the two treatment arms among patients who underwent upfront surgery (HR = 0.52; 95% confidence interval [CI] = 0.40–0.69). Patients randomly assigned to olaparib plus bevacizumab had an additional 11.4 months of median progression-free survival vs bevacizumab alone (29.6 vs 18.2 months).

“Patients received the first cycle of chemotherapy a median of 7 months before randomization. Thus, patients in the combination therapy who underwent upfront surgery experienced a total median time without disease progression of 36.6 months,” said Dr. Grimm.

Although not quite as effective, patients who underwent interval surgery also benefited from the combination maintenance therapy with a reduction of risk of death or disease progression of 44% compared to bevacizumab alone, Dr. Grimm reported.

When the timing of surgery was combined with residual disease status, the benefits of the combination therapy were even more dramatic. Patients randomly assigned to olaparib plus bevacizumab following upfront surgery who achieved complete surgical resection had a median progression-free survival of 39.3 months vs 22.1 months with bevacizumab alone (HR = 0.47; 95% CI = 0.29–0.75). As Dr. Grimm reported, 69.4% of patients were progression-free at 2 years in the olaparib-plus-bevacizumab arm vs 42.6% in the control arm.

Although the difference in progression-free survival was, again, smaller than for upfront surgery, patients who underwent interval surgery who achieved complete debulking also benefited from combination therapy vs bevacizumab alone (HR = 0.61; 95% CI = 0.41–0.91).

Finally, improvement in progression-free survival with olaparib plus bevacizumab vs bevacizumab alone was observed even among patients with visible residual disease after both upfront and interval surgery. However, Dr. Grimm acknowledged, these last results should be interpreted with caution, given the small number of patients in this subgroup.

Regardless of the timing of surgery or residual disease status after surgery, maintenance olaparib plus bevacizumab improved progression-free survival compared with bevacizumab alone, Dr. Grimm concluded. 

DISCLOSURE: Dr. Grimm has received consulting or speaker fees from Amgen, AstraZeneca, Celgene, Clovis, GSK/Tesaro, MSD, PharmaMar, Roche, and Vifor Pharma and research funding from Meda Pharma and Roche Diagnostics. Dr. Ray-Coquard has received honoraria from AbbVie, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genmab MSD Oncology, PharmaMar, Pfizer, Roche, and Tesaro; has served as a consultant or advisor AbbVie, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Deciphera, Genmab, MSD Oncology, Pfizer, PharmaMar, Roche, and Tesaro; has received research funding from Bristol-Myers Squibb and MSD Oncology; and has been reimbursed for travel, accommodations, or other expenses by Advaxis, AstraZeneca, Bristol-Myers Squibb, Clovis, GSK, PharmaMar, Roche, and Tesaro.

REFERENCES

1. Ray-Coquard I, Desauw C, Zamagni C, et al: 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. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Webinar 2. Presented April 29, 2020.

2. 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 with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy plus bev. ESMO Congress 2019. Abstract LBA2_PR. Presented September 27, 2019.

3. Grimm C, Gladieff L, Harter P, et al: Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients with newly diagnosed advanced high-grade ovarian cancer: Efficacy by timing of surgery and residual tumor status in the phase III PAOLA-1 trial. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Webinar 2. Presented April 29, 2020.