The combination of venetoclax and fulvestrant failed to improve overall outcomes vs fulvestrant alone in patients with locally advanced or metastatic estrogen receptor–positive, HER2-negative breast cancer who had previously received a CDK4/6 inhibitor.
The combination of venetoclax (Venclexta) and fulvestrant (Faslodex) failed to improve overall outcomes vs fulvestrant alone in patients with locally advanced or metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer who had previously received a CDK4/6 inhibitor, according to findings from the phase 2 VERONICA trial (NCT03584009) that were presented during the 2021 ASCO Annual Meeting.
At a median follow-up of 9.9 months, the clinical benefit rate (CBR) was 11.8% (95% CI, 4.44%-23.87%) with venetoclax/fulvestrant vs 13.7% (95% CI, 5.7%-26.26%) with fulvestrant alone, translating 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, FRACP, MBBS, PhD, joint head of the Stem Cells and Cancer Division at The Walter and Eliza Hall Institute of Medical Research, said in a virtual presentation of the data.
Despite the use of the combination of a CDK4/6 inhibitor and chemotherapy, which has become the standard frontline therapy for patients with metastatic ER-positive, HER2-negative breast cancer, disease progression is inevitable.
BCL-2 is a pro-survival protein that is overexpressed in the majority of primary and relapsed ER-positive breast cancers. The BCL-2 inhibitor venetoclax has shown promising activity in patients with endocrine-naïve, ER-positive, BCL-2–positive metastatic breast cancer.
To that end, investigators evaluated the activity of adding the BCL-2 inhibitor to fulvestrant in patients with progressive ER-positive, HER2-negative disease.
Eligibility criteria stipulated that females, 18 years of age or older, had to have locally advanced or metastatic ER-positive, HER2-negative breast cancer, 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 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.
CBR, defined as the total complete response (CR), partial response (PR), and stable disease rate after at least 24 weeks, served as the primary end point of the study. 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.
The primary analysis took place on August 5, 2020, and the updated analysis took place in April 2021.
Regarding baseline demographics, the median age was 58 years in the venetoclax arm vs 59.5 years in the fulvestrant-alone arm. Approximately half of all patients had an ECOG performance status of 0 in both arms, at 54.9% and 59.6%, respectively. Moreover, in both arms, the majority of patients were White (78.4% vs 88.5%, respectively), had ductal histology (78.4% vs 65.4%, respectively), at least 1 visceral metastatic lesion (92.2% vs 82.7%, respectively), and 1 prior line of endocrine therapy in the metastatic setting (80.4% vs 82.7%, respectively).
All patients had received prior endocrine therapy in the venetoclax and fulvestrant-alone arms, whereas approximately half had received adjuvant chemotherapy (58.8% vs 51.9%, respectively), and less than a quarter had received prior neoadjuvant chemotherapy (23.5% vs 13.5%, respectively).
The median duration of exposure to prior treatment with a CDK4/6 inhibitor in the metastatic setting was 15 months in the venetoclax arm vs 16.5 months in the fulvestrant-alone arm, with palbociclib (Ibrance; 56.9% vs 75%, respectively) and ribociclib (Kisqali; 43.1% vs 25%, respectively).
Regarding BCL-2 status, more patients had high expression in the venetoclax and fulvestrant-alone arms (64.7% vs 65.4%, respectively) than low expression (35.3% vs 34.6%, respectively).
Biomarker status in the venetoclax and fulvestrant-alone arms, respectively, indicated the presence of mutations in the PIK3CA (39.6% vs 30.4%), ESR1 (43.8% vs 41.3%), TP53 (47.9% vs 34.8%), and RB1 (18.8% vs 8.7%) genes.
Additional 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-alone arm (HR, 2.56; 95% CI, 1.11-5.89; P = .0218). The updated analysis showed comparable results, with a numerically lower hazard ratio of 1.85 (95% CI, 1.01-3.39).
Notably, similar CBR and PFS was observed between arms irrespective of BCL-2 expression.
However, increased CBR and PFS was reported in the PIK3CA wild-type subgroup in an exploratory analysis. Here, the CBR was 20.7% in the venetoclax arm (n = 29) vs 9.7% in the fulvestrant-alone arm (n = 31). The median PFS was 3.71 months (95% CI, 1.94-4.53) vs 1.87 (95% CI, 1.74-3.55), respectively (HR, 0.66; 95% CI, 0.38-1.17; P = .1549).
A higher number of deaths was reported in the venetoclax arm vs the fulvestrant-alone 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.
The safety profile of the combination was consistent with the known safety profile of each agent alone, and no new signals were identified.
The occurrence of at least 1 adverse effect (AE) was reported in 94% of patients in the venetoclax arm vs 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.
“It remains unclear whether a BCL-2 inhibitor would be effective in an endocrine therapy–responsive, CDK4/6 inhibitor–naïve setting,” concluded Lindeman.