Combination Cediranib Plus Olaparib Improves PFS in Platinum-Resistant Ovarian Cancer

Nicoletta Colombo, MD

Cediranib in combination with olaparib (Lynparza) demonstrated an improvement in progression-free survival (PFS) when used as treatment for patients with platinum-resistant ovarian cancer (PROC). However, the difference in PFS compared with chemotherapy did not achieve statistical significance, according to a randomized trial.¹

Continuous treatment with the VEGF inhibitor cediranib and the PARP inhibitor olaparib led to a median PFS of 5.7 months as compared with 3.1 months with weekly paclitaxel. The difference represented a 24% decrease in the hazard for disease progression or death but did not significantly distinguish itself from paclitaxel (90% CI, 0.49-1.17;P= .29). The combination appeared even more active in patients with germline (g)BRCAwild-type tumors, resulting in a 37% reduction in the hazard ratio versus paclitaxel.

Intermittent therapy with the combination led to a median PFS of 3.8 months, Nicoletta Colombo, MD, of the European Oncology Institute in Milan, reported at the 2019 ESMO Congress.

“The BAROCCO trial included a difficult-to-treat population with a high unmet need: 59% of the patients had received 3 or more lines of therapy and their median platinum-free interval was less than 3 months,” said Colombo. “Although not statistically significant, the continuous administration [of the combination] shows a promising trend for improved progression-free survival, particularly in the germlineBRCAwild-type population.

“The continuous administration of cediranib and olaparib is active in platinum-resistant ovarian cancer patients, with a clinical benefit observed in 85% of patients. The regimen was well tolerated with few severe side effects,” added Colombo.

Despite recent advances in the treatment of platinum-sensitive ovarian cancer, PROC continues to represent a high unmet need. The disease is associated with a median PFS of 3 to 4 months with weekly paclitaxel, which is the most effective chemotherapy regimen, said Colombo.

The FDA approved single-agent olaparib for relapsedgBRCA-mutant ovarian cancer, but limited data exist regarding the activity of PARP inhibitors inBRCAwild-type PROC.

Evidence does exist for PARP inhibitor activity beyondgBRCA-mutant disease when combined with an angiogenesis inhibitor. Cediranib/olaparib led to a fourfold increase in median PFS compared to olaparib monotherapy in patients withgBRCAwild-type ovarian cancer.²Bevacizumab (Avastin) and niraparib (Zejula) more than doubled median PFS ingBRCAwild-type ovarian cancer as compared with niraparib alone.³

“The combination of cediranib and olaparib may have a synergistic effect,” said Colombo. “Molecular pharmacology studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functionalBRCAness that favors the selective activity of the PARP inhibitior.”

With that background, investigators at multiple centers in Italy performed a randomized phase II trial comparing weekly paclitaxel with 2 different cediranib/olaparib regimens. All patients received olaparib at 300 mg twice daily, as well as cediranib at 20 mg daily. However, one group of patients received cediranib 7 days a week (continuous) and a second group received the VEGF inhibitor 5 days a week (intermittent). Patients randomized to paclitaxel received 80 mg/m²weekly.

Investigators assumed a median PFS of 3.4 months with paclitaxel and projected that the combination would reduce the hazard ratio by 49% (3.3-month improvement).

The trial included 123 patients, randomized 1:1:1 to the 3 treatment arms. The groups were balanced with respect to distribution of baseline characteristics. Data were stratified by BRCA status (89% wild-type or unknown), prior antiangiogenic therapy (53%), and prior lines of chemotherapy (three or more, 59% ).

Colombo said 12 patients allocated to paclitaxel withdrew from the study following randomization, leaving 29 for data analysis. Subsequently, 95% to 100% of patients in all 3 groups dropped out, primarily because of disease progression (80%-90%). Three patients in the paclitaxel group withdrew because of adverse events, as did 3 in the continuous-therapy arm and 1 in the intermittent arm.

The 24% relative difference in the PFS hazard between the continuous and paclitaxel arms included a 28.2% absolute difference in favor of the combination at 2 months and 15.7% difference at 4 months. Thereafter, the survival curves started to converge, but continuous combination therapy maintained an advantage throughout. The comparison of paclitaxel versus intermittent combination therapy produced a hazard ratio of 1.08 (P= .76).

A subgroup analysis of PFS showed that continuous treatment with the combination was particularly active in patients with no more than 2 prior lines of chemotherapy (HR, 0.47) and those with no prior antiangiogenic therapy (HR, 0.58), as well as the patients withgBRCAwild-type or unknown status (HR, 0.63).

Analysis of objective response favored paclitaxel (33.3%) over the continuous (17.9%) and intermittent (11.4%) combination arms, whereas stable disease occurred two to three times as often with continuous (66.7%) and intermittent (51.4%) combination therapy (20.8% for paclitaxel).

The proportion of patients with progressive disease as best response was 45.8% in the paclitaxel group, 15.4% with the continuous combination arm, and 37.1% with the intermittent combination arm.

Combination therapy (both arms) was associated with substantially more drug-related adverse events, including diarrhea (51%-58%), nausea (50%-51%), vomiting (37%-38%), fatigue (40%-46%), and hypertension (18%-29%). The most common grade ≥3 treatment-related adverse events associated with the combination were anemia (10%-13%), fatigue (10%), and hypertension (12%-13%).

References:

1. Colombo N, Nicoletto M, Benedetti Panici P, et al. BAROCCO: A randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA58.
2. Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.Ann Oncol. 2019;30(4):551-557. doi: 10.1093/annonc/mdz018.
3. Mirza MR, Åvall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial [published online August 29, 2019].Lancet Oncol. doi: 10.1016/S1470-2045(19)30515-7.