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Venetoclax in combination with enzalutamide displayed a favorable safety profile as a treatment regimen for mCRPC.
Enzalutamide (Xtandi) in combination with venetoclax (Venclexta) demonstrated an acceptable safety profile, was well tolerated, and no dose-limiting toxicities (DLTs) were observed in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase Ib study (NCT03751436), published in Cancer Chemotherapy and Pharmacology.1
No DLTs were observed in patients from the trial who received enzalutamide in combination with venetoclax (n = 10), additionally most treatment-related adverse effects (TRAEs) in the trial were grade 1 or 2. Common grade 1 TRAEs included nausea, fatigue, and headaches, which occurred in 30%, 40%, and 20% of patients respectively. Common grade 2 TRAEs from the trial included fatigue, arthralgia, and anorexia which occurred in 40%, 10%, and 10% of patients respectively. Grade 3 TRAEs consisted of thrombocytopenia and fatigue, which occurred in 10% of patients each.
“This favorable safety profile is encouraging, as it suggests the potential for combining androgen receptor pathway inhibitors with venetoclax without excessive toxicity,” lead study author Stuthi Perimbeti, MD, MBBS, MPH, and coauthors wrote in the publication.
Perimbeti is an assistant professor in the Department of Medicine at the Penn State Cancer Institute in Hershey, Pennsylvania.
The study enrolled patients who were at least 18 years old with a histologically or cytologically documented diagnosis of prostate cancer in addition to documented mCRPC that exhibited progressive disease. Patients also needed to have an ECOG performance status of 0 or 1 and adequate organ function.
If patients had active hematological malignancies, previous BCL2 inhibitor treatment, untreated or active central nervous system metastases or anticancer therapy within 21 days before the first cycle of treatment they were not included in the trial.
In the single-arm, open label, dose-escalation study, patients received a standard 160-mg oral dose of enzalutamide each day for the first cycle of 28 days. Following the first cycle, patients were administered venetoclax at a starting dose of 400 mg which then escalated to 600 mg and then finally to 800 mg across 3 different cohorts of patients. Venetoclax dosages were administered concurrently with 160 mg of enzalutamide daily in 28-day cycles.
The primary end points of the trial were to determine the maximum tolerated dose, the recommended phase 2 dose, and the safety and tolerability profile of enzalutamide and venetoclax in patients with mCRPC.
Baseline characteristics of the trial indicated that patients had a median age of 71 years (range, 59-76). ECOG performance statuses of patients in the trial were split, where one half of patients had an ECOG performance status of 1 (n = 5; 50%), whereas the other half of patients had an ECOG performance status of 0 (n = 5; 50%). All patients in the trial had received prior chemotherapy (n = 10; 100%), whereas less patients had undergone prior surgery (n = 4; 40%). Almost all patients had received prior androgen receptor targeted therapy (n = 9; 90%), whereas a smaller majority of patients had received prior radiation (n = 7; 70%).
The trial’s secondary end points were a 50% or greater reduction in prostate-specific antigen, radiographic progression-free survival (PFS), overall response rate, overall survival (OS), and duration of response.2 Patients in the trial had achieved an estimated median PFS of 2.6 months (95% CI, 1.8-9.1), whereas the estimated median OS was 18.8 months (95% CI, 6.4-28.7).1 Almost half of the patients achieved stable disease (n = 4; 40%), and slightly more than half experienced progressive disease (n = 6; 60%).
“[Although] the study was primarily focused on safety and tolerability, preliminary efficacy data showed promising signals,” Perimbeti, MD, MBBS, MPH, and coauthors wrote in the paper.
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