{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:10:17Z","timestamp":1768569017481,"version":"3.49.0"},"posted":{"date-parts":[[2025,4,22]]},"group-title":"Oncology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Castration and enzalutamide induce BCL-2 to drive therapy resistance in prostate cancer (PCa). 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 mg\/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 400 mg\/d; DL2 600 mg\/d; and DL3 800 mg) were evaluated using a 3+3 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 weeks (range: 8-140 weeks). Treatment-related adverse events (TRAEs) were mostly grade 1-2, and Grade 3 TRAEs included hypertension (20%), 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 months (95% CI 5-28 months) and median time to next systemic therapy (TNST) was 5 months (95% CI 1-35 months). Pharmacokinetic results revealed sub-therapeutic 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-therapeutic venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients.<\/jats:p>\n                  <jats:p>\n                    Clinical trial ID:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03751436\">NCT03751436<\/jats:ext-link>\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Translational Relevance<\/jats:title>\n                  <jats:p>\n                    There are limited treatment options for mCRPC patients. Castration and androgen receptor (AR) targeted therapies cause significant cellular plasticity and exacerbate AR heterogeneity in mCRPC resulting in emergence of AR-positive (AR\n                    <jats:sup>+<\/jats:sup>\n                    ) and AR-negative (AR\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) PCa progenitor cells and metastatic foci. While AR\n                    <jats:sup>+<\/jats:sup>\n                    mCRPC can be targeted by AR pathway inhibitors (ARPIs) such as enzalutamide, AR\n                    <jats:sup>\u2212<\/jats:sup>\n                    mCRPC cannot. Based on our recent findings that castration and ARPIs upregulate BCL-2 in both AR\n                    <jats:sup>+<\/jats:sup>\n                    and AR\n                    <jats:sup>\u2212<\/jats:sup>\n                    CRPC models to drive castration resistance, here we conduct a prospective phase Ib clinical study to test that the heterogeneous AR\n                    <jats:sup>+<\/jats:sup>\n                    and AR\n                    <jats:sup>\u2212<\/jats:sup>\n                    mCRPC can be holistically targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.22.25326208","type":"posted-content","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T01:55:16Z","timestamp":1745373316000},"source":"Crossref","is-referenced-by-count":1,"title":["Phase Ib Study of Enzalutamide with Venetoclax in Patients with Metastatic Castration-Resistant Prostate 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