FDA Grants Priority Review to Olaparib Plus Bevacizumab for Frontline Ovarian Cancer

The supplemental New Drug Application for olaparib (Lynparza), a PARP inhibitor, in combination with bevacizumab (Avastin) has been granted Priority Review by the FDA as maintenance treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy, based on the results from the phase III PAOLA-1 trial, according to a press release from AstraZeneca and Merck & Co, Inc.¹

The randomized, double-blind trial PAOLA-1 trial, which was recently published in theNew England Journal of Medicine,showed that the addition of olaparib to bevacizumab in the overall study population reduced the risk of disease progression or death by 41% compared with bevacizumab (HR, 0.59; 95% CI, 0.49-0.72;P<.001). The median progression-free survival (PFS) observed with olaparib plus bevacizumab was 22.1 months versus 16.6 months with bevacizumab.²

In patients withBRCA-mutated ovarian cancer, the median PFS was 37.2 months in the combination group compared with 21.7 months in the placebo group (HR, 0.31; 95% CI, 0.20-0.47). In patients who did not have aBRCAmutation, the median PFS was 18.9 with the olaparib combination and 16.0 months with bevacizumab (HR, 0.71; 95% CI, 0.58-0.88).

In a subset of patients with homologous recombination deficiency (HRD)-positive, the median PFS was 37.2 months in the olaparib combination group and 17.7 months in the placebo group (HR, 0.33; 95% CI, 0.25-0.45). Among those with HRD-positive tumors who did not haveBRCAmutations, the median PFS was 28.1 months in the olaparib group compared with 16.6 months in the placebo group (HR, 0.43; 95% CI, 0.28-0.66).

Another subset of patients with tumors that were negative for HRD, or those with an unknown HRD status, the median PFS was 16.9 in the combination group and 16.0 months in the monotherapy group (HR, 0.92; 95% CI, 0.72-1.17). In patients with HRD-negative tumors, the median PFS was 16.6 months and 16.2 months, respectively (HR, 1.00; 95% CI, 0.75-1.35).

The overall survival data had not yet matured at the time do data cutoff, which was March 22, 2019.

Both olaparib and bevacizumab have safety and tolerability profiles that were consistent with previous clinical trials. The most common adverse events (AEs) seen in patients who received the olaparib combination were fatigue (53%), nausea (53%), hypertension (46%), lymphopenia (24%), vomiting (22%), and arthralgia (22%). Hypertension and arthralgia were the only AEs that occurred more frequently in patients treated with bevacizumab alone than with the olaparib combination at rates of 60% and 24%, respectively. Other common AEs observed in the placebo group were otherwise consistent with olaparib: fatigue (32%), nausea (22%), anemia (10%), lymphopenia (9%), and vomiting (11%).¹

In the olaparib plus bevacizumab group, 57% of patients develop grade 3 or higher AEs compared with 51% of patients treated with bevacizumab alone. The grade 3 or higher AEs in the combination group versus the placebo group included hypertension (19% vs 30%), anemia (17% vs <1%), lymphopenia (7% vs 1%), fatigue (5% vs 1%), neutropenia (6% vs 3%), nausea (2% vs 1%), diarrhea (2% each), leukopenia (2% vs 1%), vomiting (1% vs 2%) and abdominal pain (1% vs 2%). Treatment was interrupted in 54% of the patients who were given olaparib plus bevacizumab and 24% of those given bevacizumab alone. Doses were reduced in 41% of patients in the combination group and 7% of those in the monotherapy group. Also, 20% of patients taking olaparib plus bevacizumab and 6% of those treated with bevacizumab alone discontinued treatment.

Patients with newly diagnosed advanced International Federation of Gynecology and Obstetrics (FIGO) Stage III to IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab in the received either olaparib 300 mg twice daily plus standard-of-care bevacizumab or bevacizumab alone. The primary end point of the study was PFS. The study also evaluated secondary end points including OS, time to earliest progression, PFS2, time to start of first subsequent therapy or death, time to start of second subsequent therapy or death, and safety and tolerability.¹

If the FDA grants approval to olaparib for the treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab, it will be the fourth indication for the drug in ovarian cancer.

Olaparib has prior approvals for the maintenance treatment of adult 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 first-line platinum-based chemotherapy; for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy; and for the treatment of adult patients with deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

References

1. Lynparza (olaparib) regulatory submission granted priority review in US for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer [news release]. Kenilworth, NJ: AstraZeneca and Merck & Co., Inc.; January 13, 2020. https://bit.ly/386gpdR. Accessed January 13, 2020.
2. Ray-Coquard I, Oautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med 2019;381(25):2416-2428. doi: 10.1056/NEJMoa191136.