«Data analysis is negative. Venetoclax added to fulvestrant did not improve clinical benefit rate, progression-free survival nor overall survival», lead VERONICA study author Geoffrey Lindeman of The Walter and Eliza Hall Institute of Medical Research in Melbourne said, in a virtual presentation of the data during the latest virtual ASCO congress (https://www.asco.org/): the phase II study of the association of the BCL-2 inhibitor and the anti-estrogen failed to show the awaited results.
Venetoclax is a BCL-2 inhibitor; BCL-2 is a pro-survival protein that is overexpressed in the majority of primary and relapsed ER-positive breast cancers. Researchers combined venetoclax to fulvestrant, a drug that blocks and damages estrogen receptors, in women with locally advanced or metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer, because venetoclax has previously shown promising activity in patients with endocrine-naïve, ER-positive, BCL-2–positive metastatic breast cancer. The standard first-line therapy for these patients is the combination of a CDK4/6 inhibitor and endocrine therapy, but disease progression is inevitable and that is why different treatments are under evaluation. The association of venetoclax and fulvestrant was tested in patients who received no more than 2 prior lines of therapy in the locally advanced or metastatic setting without chemotherapy, and received a CDK4/6 inhibitor at least 8 weeks before enrollment. They all were BCL-2 positive and had received prior endocrine therapy, half had received adjuvant chemotherapy and less than a quarter had received prior neoadjuvant chemotherapy; patients in control arm were treated with fulvestrant only.
Investigators evaluated, in addition to safety, tolerability and pharmacokinetics, the clinical benefit rate (defined as the total complete response, partial response and stable disease rate) after at least 24 weeks, disease free survival, overall survival, objective response rate and duration of response. The safety profile of the combination was consistent with the known safety profile of each agent alone, and no new signals were identified; however, irrespective of BCL-2 expression, there were no significant differences in all endpoints between venetoclax-fulvestrant and fulvestrant alone arms. A negative result that does not warrant further investigation of the association of venetoclax and fulvestrant in ER–positive, HER2-negative breast cancer. «It remains unclear whether a BCL-2 inhibitor would be effective in an endocrine therapy–responsive, CDK4/6 inhibitor–naïve setting», Lindeman concluded.