BARCELONA – (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.
The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63,, reported at the European Society of Medical Oncology Congress.
Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m2 of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.
The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.
“Surprisingly, the intermittent regimen did not perform as well,” she noted.
Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.
Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).
As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.
“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”
Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.
The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.
“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.
Additionally,is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.
Single-agent olaparib wasby the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.
Findings from thepresented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the , the ORR in gBRCAwt PROC was just 3%
“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.
“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic 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 inhibitors,” she explained.
Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.
BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.
However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.
Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.
Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.
Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”
“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.
Invited discussant, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.
“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.
He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.
The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.
SOURCE: Colombo N et al. ESMO 2019, . Ann Oncol. 2019;30:suppl 5.