Niraparib demonstrated clinically relevant activity among women with heavily pretreated ovarian cancer, particularly those with homologous recombination deficiency-positive, platinum-sensitive disease, according to findings from the phase 2 QUADRA study published in The Lancet Oncology.
The results, which also showed no new safety signals, support extending the use of poly(ADP-ribose) polymerase (PARP) inhibitors to a wider population of women with late-line ovarian cancer, including those without BRCAmutations, according to the researchers.
“This is another piece of the puzzle that helps our patients live longer,” Kathleen Moore, MD, associate director of clinical research at Stephenson Cancer Center at University of Oklahoma College of Medicine, said in a press release. “There haven’t been a lot of studies done on patients without BRCA mutations who have received four, five, six or more lines of chemotherapy. That’s who this trial sought to study.”
As many as 25% of women without a BRCA mutation can develop homologous recombination deficiency (HRD), which means they can derive benefits from PARP inhibitors such as niraparib (Zejula, Tesaro).
In the multicenter, open-label, single-arm, phase 2 study, Moore and colleagues enrolled 463 women aged 18 years and older (median age, 65 years; range, 29-91) with metastatic, relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone at least three prior chemotherapy regimens. Patients had ECOG performance status of 0 or 1 and adequate organ function and had received a median four (interquartile range [IQR], 3-5) previous lines of treatment.
The study was conducted at 56 sites in the United States and Canada.
Women received 300 mg oral niraparib once daily starting on day 1 and continuously through each 28-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The prevalence of confirmed overall response among women with HRD-positive tumors — including those with and without BRCA mutations — who showed sensitivity to their last platinum-based therapy served as the study’s primary objective. Efficacy analyses also were conducted among all dosed patients with evaluable disease at baseline.
Median follow-up for OS was 12.2 months (IQR, 3.7-22.1).
Among all women who initiated treatment, 151 (33%) had platinum-resistant disease and 161 (35%) had platinum-refractory disease.
Results showed 13 of 47 women with platinum-sensitive, HRD-positive tumors naive to PARP inhibitors demonstrated overall response (27.65%; 95% CI, 15.6-42.6). These women had median PFS of 5.5 months (95% CI, 3.5-8.2) and median duration of response of 9.2 months (95% CI, 5.9 to not estimable), and 68% (95% CI, 53-81) achieved disease control.
“We don’t normally see response rates of more than 10% in women who have had four, five and six chemotherapy treatments,” Moore said in the press release. “So, a 27% response, especially given that these were not all women with BRCA mutations, was a nice signal that these patients can still benefit from PARP inhibitor use.”
Median OS was 26 months (95% CI, 18.1 to not estimable) among women with BRCA mutations, 19 months (95% CI, 14.5-24.6) among women with HRD-positive tumors and 15.5 months (95% CI, 11.6-19) among women with HRD-negative tumors.
The most prevalent drug-associated grade 3 or worse adverse events included anemia (24%) and thrombocytopenia (21%). Researchers observed serious treatment-emergent adverse events in 43% of all women, including small intestine obstruction (7%), thrombocytopenia (7%) and vomiting (6%). One treatment-related death occurred due to gastric hemorrhage.
The researchers reported several limitations to their study, including its single-arm, nonrandomized design. Additionally, although the study was powered for the primary outcome, it was not powered for analyses of subgroups.
“We think [these data support] the expansion of niraparib to be more inclusive of patients. PARP inhibitors work best in women with BRCA mutations, but they can still work well in women without the mutation,” Moore said in the release. “Niraparib really makes sense for a much broader population.” – by Jennifer Byrne
Disclosures: Moore reports honoraria or advisory board fees from AstraZeneca, Clovis Technology, Genentech, ImmunoGen, Janssen, Roche, Tesaro and VBL Therapeutics. Please see the study for all other authors’ relevant financial disclosures.