Venetoclax (Venclexta) plus fulvestrant (Faslodex) did not provide superior outcomes compared to fulvestrant monotherapy among patients with locally advanced or metastatic ER–positive, HER2-negative breast cancer.
Venetoclax (Venclexta) plus fulvestrant (Faslodex) did not provide superior outcomes compared to fulvestrant monotherapy among patients with locally advanced or metastatic estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with a CDK4/6 inhibitor, according to the results of the phase 2 VERONICA trial presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.
With median follow-up of 9.9 months, the clinical benefit rate (CBR) was 11.8% (95% CI, 4.44%-23.87%) with venetoclax/fulvestrant compared with 13.7% (95% CI, 5.7%-26.26%) with fulvestrant monotherapy, which translates to a risk difference of -1.96% (95% CI, -16.86%-12.94%).
“The primary analysis of VERONICA revealed a largely endocrine-refractory population of patients. Venetoclax added to fulvestrant did not improve CBR or progression-free survival [PFS], [nor did] overall survival [OS] favor [the combination],” lead study author Geoffrey J. Lindeman, MD, joint head of Stem Cells and Cancer Division at The Walter and Eliza Hall Institute of Medical Research, said during the presentation.
The study examined the addition of a BCL-2 inhibitor to fulvestrant in patients with progressive ER-positive, HER2-negative disease.
The study enrolled patients 18 years of age or older with locally advanced or metastatic ER-positive, HER2-negative breast cancer, who received 2 or fewer lines of therapy in the locally advanced or metastatic setting without chemotherapy, received a CDK4/6 inhibitor at least 8 weeks before enrollment, and who have measurable disease.
Patients were randomized 1:1 to 800 mg of oral, daily venetoclax (n = 51) plus 500 mg of intramuscular fulvestrant on day 1 and 15 of cycle 1 and day 1 of each 28-day cycle thereafter or fulvestrant alone (n = 52). Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end.
The primary endpoint of the study was CBR, defined as the total complete response (CR), partial response (PR), and stable disease rate after at least 24 weeks. Secondary end points included PFS, OS, objective response rate (ORR), defined as the total CR and PR rate, and duration of response (DOR).
Additional end points included safety and tolerability, biomarker analysis, pharmacokinetics, and patient-reported outcomes.
All patients had received prior endocrine therapy in the venetoclax and fulvestrant-monotherapy cohorts, whereas approximately half had received adjuvant chemotherapy (58.8% vs 51.9%, respectively), and less than one-quarter had received prior neoadjuvant chemotherapy (23.5% vs 13.5%, respectively).
Results demonstrated that the ORR was 3.9% in the venetoclax arm vs 5.9% in the fulvestrant-alone arm and consisted all of PRs. The median PFS was 2.69 months (95% CI, 1.94-3.71) in the venetoclax arm vs 1.94 months (95% CI, 1.84-3.55) in the fulvestrant-alone arm (HR, 0.94; 95% CI, 0.61-1.45; P = .7853). The 6-month PFS rates were 12.3% vs 18.8%, respectively.
The OS data were not mature at the time of the primary analysis but did not favor the venetoclax arm. The median OS was 16.76 months (95% CI, 10.12-not evaluable [NE]) in the venetoclax arm vs NE (95% CI, 16-NE) in the fulvestrant-monotherapy group (HR, 2.56; 95% CI, 1.11-5.89; P = .0218).
A higher number of deaths was reported in the venetoclax arm compared with the fulvestrant-monotherapy arm primarily because of progressive disease at least 28 days after the last dose of study treatment. A similar trend was reported in the updated analysis.
At least 1 adverse effect (AE) was reported in 94% of patients in the venetoclax arm compared with 76.5% of patients in the fulvestrant-alone arm. Grade 3 or 4 AEs were reported in 26% vs 11.8% of patients, respectively. Serious AEs occurred in 8% vs 2% of patients, respectively. One case of urosepsis leading to death occurred in the venetoclax arm but was unrelated to the study drug.
Treatment-related AEs leading to drug withdrawal occurred in 8% of patients in the venetoclax arm vs 0% of patients in the fulvestrant-alone arm. AEs leading to dose modification or interruption occurred in 44% vs 2% of patients, respectively. The most common grade 3 or 4 AEs in the venetoclax arm included fatigue (6%), neutropenia (12%), lymphopenia (4%), and dyspnea (4%) vs a 2% incidence of grade 3 or 4 fatigue in the fulvestrant-alone arm.
Lindeman GJ, Bowen R, Jerzak KJ, et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax + fulvestrant vs. fulvestrant alone in estrogen receptor-positive, HER2-negative, locally advanced, or metastatic breast cancer. J Clin Oncol. 2021;39(suppl 15):1004. doi:10.1200/JCO.2021.39.15_suppl.1004