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Purpose <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.</p> Experimental design <p>This phase Ib single-arm trial of enzalutamide (160&#xa0;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 at 400&#xa0;mg/d; DL2 at 600&#xa0;mg/d; and DL3 at 800&#xa0;mg/d) 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.</p> Results <p>A total of 10 patients were enrolled across 3 DL and no DLT was observed. Mean duration on treatment was 29&#xa0;weeks (range: 8–140&#xa0;weeks). Treatment-related adverse events (TRAEs) were mostly grade 1–2, 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&#xa0;months (95% CI 5–28&#xa0;months) and median time to next systemic therapy (TNST) was 5&#xa0;months (95% CI 1–35&#xa0;months). Pharmacokinetic results revealed sub-optimal plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2β generation and promoted BCL-2 degradation.</p> Conclusions <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.</p> Clinical trial ID <p>NCT03751436.</p>

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Phase Ib study of enzalutamide with venetoclax in patients with metastatic castration-resistant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月29日

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  • Stuthi Perimbeti,
  • Anmbreen Jamroze,
  • Dharmesh Gopalakrishnan,
  • Rohit Jain,
  • Changchuan Jiang,
  • Julianne L. Holleran,
  • Robert A. Parise,
  • Robert Bies,
  • David Quinn,
  • Kristopher Attwood,
  • Xiaozhuo Liu,
  • Kelly Green,
  • Jason S. Kirk,
  • Jan H. Beumer,
  • Dean G. Tang,
  • Gurkamal Chatta

摘要

Purpose

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.

Experimental design

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 at 400 mg/d; DL2 at 600 mg/d; and DL3 at 800 mg/d) 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.

Results

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 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-optimal plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2β generation and promoted BCL-2 degradation.

Conclusions

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.

Clinical trial ID

NCT03751436.