Cediranib/Olaparib Combo Shows Promise in Platinum-Resistant Ovarian Cancer

Article

The combination of cediranib and olaparib improved progression-free survival in patients with platinum-resistant ovarian cancer, although the difference from chemotherapy did not achieve statistical significance.

Nicoletta Colombo, MD

Nicoletta Colombo, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Nicoletta Colombo, MD

The combination of cediranib and olaparib (Lynparza) improved progression-free survival (PFS) in patients with platinum-resistant ovarian cancer (PROC), although the difference from chemotherapy did not achieve statistical significance, a randomized trial showed.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 (HR, 0.76; 90% CI, 0.49-1.17; P = .29). The combination appeared even more active in patients with germline (g) BRCA wild-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 germline BRCA wild-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 relapsed gBRCA-mutant ovarian cancer, but limited data exist regarding the activity of PARP inhibitors in BRCA wild-type PROC.

Evidence does exist for PARP inhibitor activity beyond gBRCA-mutant disease when combined with an angiogenesis inhibitor. Cediranib/olaparib led to a fourfold increase in median PFS compared to olaparib monotherapy in patients with gBRCA wild-type ovarian cancer.2 Bevacizumab (Avastin) and niraparib (Zejula) more than doubled median PFS in gBRCA wild-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 functional BRCAness 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/m2 weekly.

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 with gBRCA wild-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.

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