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We conducted a phase Ib trial to test that metastatic castration-resistant PCa (mCRPC) can be effectively targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental design<\/jats:title>\n                    <jats:p>This phase Ib single-arm trial of enzalutamide (160\u00a0mg\/d) with venetoclax in patients with progressive mCRPC assessed dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Three dose levels (DL) of venetoclax (DL1 at 400\u00a0mg\/d; DL2 at 600\u00a0mg\/d; and DL3 at 800\u00a0mg\/d) were evaluated using a 3\u2009+\u20093 design. We also analyzed enzalutamide and venetoclax pharmacokinetics and conducted pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) to determine the impact of venetoclax on BCL-2 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 10 patients were enrolled across 3 DL and no DLT was observed. Mean duration on treatment was 29\u00a0weeks (range: 8\u2013140\u00a0weeks). Treatment-related adverse events (TRAEs) were mostly grade 1\u20132, and Grade 3 TRAEs included fatigue (10%) and thrombocytopenia (10%). 1\/10 (10%) attained PSA50 response and 4\/10 (40%) had stable disease. Estimated median overall survival (OS) was 19\u00a0months (95% CI 5\u201328\u00a0months) and median time to next systemic therapy (TNST) was 5\u00a0months (95% CI 1\u201335\u00a0months). Pharmacokinetic results revealed sub-optimal plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2\u03b2 generation and promoted BCL-2 degradation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Enzalutamide with venetoclax has an acceptable toxicity profile in patients with mCRPC. Despite sub-optimal venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial ID<\/jats:title>\n                    <jats:p>NCT03751436.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00280-025-04840-2","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T02:58:25Z","timestamp":1764385105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phase Ib study of enzalutamide with venetoclax in patients with metastatic castration-resistant prostate cancer"],"prefix":"10.1007","volume":"95","clinical-trial-number":[{"clinical-trial-number":"nct03751436","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Stuthi","family":"Perimbeti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anmbreen","family":"Jamroze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmesh","family":"Gopalakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne L.","family":"Holleran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Parise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Bies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher","family":"Attwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhuo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S.","family":"Kirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"Beumer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean G.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurkamal","family":"Chatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"4840_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3322\/caac.21871","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A (2025) Cancer statistics, 2025. 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