Olaparib plus durvalumab and bevacizumab led to prolonged survival and disease control without causing additive toxicity in patients with non-germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer.
Susana Banerjee MBBS, PhD, FRCP
Olaparib (Lynparza) plus durvalumab (Imfinzi) and bevacizumab (Avastin) led to prolonged survival and disease control without causing additive toxicity in patients with non-germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer, according to updated findings from the phase 1/2 MEDIOLA trial (NCT02734004).1
At a median follow-up for 31.9 months, the median overall survival (OS) with the triplet therapy (n = 31) was 31.9 months (95% CI, 22.1–not calculable [NC]); the 12- and 24-month OS rates were 96.8% and 64.5%, respectively. The 56-week disease control rate (DCR) was 38.7% (95% CI, 24.1%-55.0%).
At a median follow-up of 23.2 months, the combination of olaparib and durvalumab alone (n = 32) led to a median OS of 26.1 months (95% CI, 18.7-NC), and the 12- and 24-month OS rates were 77.6% and 50.8%, respectively. The 56-week DCR was 9.4% (95% CI, 2.6%-22.5%).
“Olaparib plus durvalumab and bevacizumab demonstrated encouraging clinical activity in women with non-germline BRCA-mutant, platinum-sensitive, relapsed ovarian cancer,” lead study author and a consultant medical oncologist and Research Lead for the Gynaecology Unit at the Royal Marsden in London, United Kingdom, Susana Banerjee, MBBS, PhD, FRCP, said in a presentation of the data. “Findings warrant further investigation of the triplet combination as a non-chemotherapy treatment for non-germline BRCA-mutant ovarian cancer.”
To be eligible for enrollment, patients had to have confirmed non-germline BRCA-mutant, high-grade serous, platinum-sensitive relapsed ovarian cancer and have received between 1 and 2 lines of prior platinum-based chemotherapy and be naïve to PARP inhibitors and immune-oncology agents.
Patients were enrolled into 1 of 2 cohorts where they received either 300 mg of oral olaparib twice daily plus 1.5 g of intravenous (IV) durvalumab every 4 weeks and 10 mg/kg of IV bevacizumab every 2 weeks or 300 mg of olaparib and durvalumab in the same schedule.
The primary end points were the 24-week DCR rate as well as safety and tolerability. Secondary end points included OS, 56-week DCR rate, progression-free survival (PFS) by RECIST v1.1 criteria, objective response rate (ORR) by RECIST v1.1 criteria, and duration of response. Exploratory end points included assessment of tumor genetics and immunology biomarkers.
In the triplet arm, the median patient age was 64 years (range, 33-77), and most patients were White (64.5%), had platinum sensitivity for 6 to 12 months (54.8%), and received 1 prior line of chemotherapy (64.5%).
In the doublet arm, the median patient age was 68.5 years (range, 40-86), and most patients were White (75.0%), had platinum sensitivity for more than 12 months (56.3%), and received 1 prior line of chemotherapy (75.0%).
At the final data cutoff, no patients remained on treatment in the combination arm, whereas 16.1%, 12.9%, and 6.5% of patients in the triplet arm remained on olaparib, durvalumab, and bevacizumab, respectively.
Prior data showed that the ORR was 34.4% (95% CI, 18.6%-53.2%) with the doublet vs 87.1% (95% CI, 70.2%-96.4%) with the triplet.2 The median PFS was 5.5 months (95% CI, 3.6-7.5) and 14.7 months (95% CI, 10-18.1), respectively.
“Previous exploratory analyses showed a high ORR in the triplet cohort and suggested that this was not driven by differences in genomic instability status [GIS],” the authors wrote. “Review of PFS and OS outcomes did not identify any clear relationship based on GIS or PD-L1 in this limited dataset. Further investigations are warranted.”
The toxicity profile of the doublet and triplet was similar to that expected of each agent alone and displayed no new safety signals with additional follow-up.
In the triplet arm, 61.3% of patients experienced grade 3 or greater adverse effects (AEs), and serious AEs occurred in 19.4% of patients. In the doublet arm, 65.6% of patients experienced grade 3 or greater AEs, and serious AEs occurred in 25.0% of patients.
Grade 3 or greater adverse effects reported in at least 2 patients in the triplet and doublet cohorts, respectively, included anemia (19.4% vs 21.9%, respectively), hypertension (16.1% vs 3.1%), fatigue (6.5% vs 6.3%), lipase increase (6.5% vs 6.3%), febrile neutropenia (6.5% vs 3.1%), neutropenia (3.2% vs 6.3%), and white blood cell count decrease (6.5% vs 0%).
AEs leading to discontinuation of any study drug occurred in 32.3% of patients in the triplet arm vs 3.1% of those in the doublet arm.
Notably, no deaths occurred in the triplet arm vs 1 in the doublet arm.
The combination of olaparib plus durvalumab and bevacizumab is now under investigation as frontline maintenance therapy in patients with non-BRCA–mutant advanced ovarian cancer in the phase 3 DUO-O/ENGOT-ov46/GOG-3025 trial (NCT03737643).