Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer Journal Article
| Authors: | Rathkopf, D. E.; Patel, M. R.; Choudhury, A. D.; Rasco, D.; Lakhani, N.; Hawley, J. E.; Srinivas, S.; Aparicio, A.; Narayan, V.; Runcie, K. D.; Emamekhoo, H.; Reichert, Z. R.; Nguyen, M. H.; Wells, A. L.; Kandimalla, R.; Liu, C.; Suryawanshi, S.; Han, J.; Wu, J.; Arora, V. K.; Pourdehnad, M.; Armstrong, A. J. |
| Article Title: | Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer |
| Abstract: | Background: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC. Patients and methods: Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). Results: Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations. Conclusions: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status. © 2024 The Authors |
| Keywords: | immunohistochemistry; signal transduction; adult; cancer chemotherapy; cancer survival; controlled study; aged; unclassified drug; major clinical study; drug tolerability; fatigue; diarrhea; drug efficacy; drug safety; hypertension; recommended drug dose; side effect; outcome assessment; prostate specific antigen; progression free survival; multiple cycle treatment; anemia; skin biopsy; protein degradation; nausea; vomiting; qt prolongation; bradycardia; tumor biopsy; dizziness; drug dose escalation; dyspnea; hypotension; multicenter study; androgen receptor; open study; maximum tolerated dose; phase 1 clinical trial; taxane derivative; drug therapy; dyspepsia; flatulence; muscle spasm; androgen deprivation therapy; ligand binding; abdominal distension; pharmacokinetic parameters; decreased appetite; androgen receptor antagonist; hypertransaminasemia; eructation; drug concentration; low fat diet; gastrointestinal pain; photopsia; human; male; article; ligand binding domain; metastatic castration resistant prostate cancer; patient history of chemotherapy; mcrpc; radiographic progression free survival; pharmacodynamic parameters; qtc interval; androgen receptor pathway inhibitor; ligand-directed degrader; bms 986365 |
| Journal Title: | Annals of Oncology |
| Volume: | 36 |
| Issue: | 1 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2025-01-01 |
| Start Page: | 76 |
| End Page: | 88 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2024.09.005 |
| PUBMED: | 39293515 |
| PROVIDER: | scopus |
| PMCID: | PMC12094577 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Dana E. Rathkopf -- Source: Scopus |
