FDA Greenlights Phase 2/3 Trial of KPG-121/Abiraterone in mCRPC


The FDA has cleared a phase 2/3 trial testing KPG-121, a novel drug, combined with abiraterone for first-line treatment of metastatic castration-resistant prostate cancer.

  • A clinical trial to evaluate the combination of a new drug called KPG-121 with abiraterone acetate (Zytiga) for treating metastatic castration-resistant prostate cancer (mCRPC) as a first-line therapy has been approved by the FDA.

  • KPG-121 is an investigational drug that targets specific proteins involved in prostate cancer cell growth and survival.

  • An earlier phase 1 study (NCT03569280) evaluated KPG-121 and showed a favorable safety profile and promising early signs of efficacy, with a 37.5% objective response rate (ORR).

The FDA has approved a phase 2/3 trial to evaluate the combination of KPG-121 with abiraterone when used as a first-line treatment of patients with mCRPC.1

KPG-121, a novel CRBN E3 ligase modulator, targets CK1α, Aiolos (IKZF3), and Ikaros (IKZF1) for rapid proteasomal degradation via the CRL4CRBN complex, leading to antiproliferative and antiangiogenic effects while enhancing immunomodulatory properties.

In preclinical studies, KPG-121 demonstrated synergy when given with abiraterone, enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) both in vitro and in vivo. Additionally, the agent, when given with androgen receptor antagonists, has shown to significantly improve antitumor efficacy in xenograft models.

Prostate cancer, bladder cancer, men's health care: © Tom - stock.adobe.com

Prostate cancer, bladder cancer, men's health care: © Tom - stock.adobe.com

In a phase 1, first-in-human study, experts sought to evaluate the safety, pharmacokinetics, and efficacy of KPG-121 when given in combination with enzalutamide, abiraterone, or apalutamide for the treatment of patients with metastatic or nonmetastatic CRPC.2 The trial utilized a standard 3+3 dose ascending design and was conducted in the US. Male patients aged 18 years and older with CRPC given stable doses of enzalutamide or abiraterone were enrolled in the study and given oral KPG-121 at a dose of 1.5 mg, 2.5 mg, 5 mg, or 10 mg once daily in 28-day treatment cycles.

Safety, including treatment-emergent adverse events (TEAEs), dose-limiting toxicity, and maximum tolerated dose, was the primary end point of the study.

According to findings presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, KPG-121 was generally well-tolerated with a favorable pharmacokinetic profile. Sixteen patients with CRPC were enrolled in the study. The mean age of patients was 70.4 years, 12 patients (75%) were White, 2 (12.5%) were Black/African American, and 2 (12.5%) were of other races.

Eight patients had RECIST-evaluable disease. Three patients (37.5%) achieved a partial response, and 3 (37.5%) had stable disease. The ORR was 37.5% (n = 3) and the disease control rate was 75.0% (n = 6).

For safety, 12 patients (75.0%) had 88 TEAEs. The most commonly reported AEs included neutropenia in 9 patients (56.3%), white blood cell count decrease in 7 (43.8%), platelet count decrease in 6 (37.5%), anemia in 4 (25.0%), thrombocytopenia in 3 (18.8%), and lymphocyte count decrease, electrocardiogram QT prolongation, and muscle spasm in 2 each (12.5% each). Additionally, there were 5 patients (31.3%) with serious AEs.

Five patients (31.3%) discontinued treatment as a result of their TEAEs, including 2 patients treated at the 2.5-mg dose, 1 treated at the 5-mg dose, and 2 treated at the 10-mg dose. COVID-19 was the cause of death of 1 patient in the study; however, it was deemed not related to the study drug.

1. FDA approved phase II/III clinical study of KPG-121 in combination with abiraterone as a first line treatment for mCRPC. News release. Kangpu Biopharmaceuticals. June 5, 2024. Accessed June 5, 2024.https://tinyurl.com/22u7tj4p
2. Devitt ME, Zuniga RM, Torres A, et al. KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study. J Clin Oncol. 2024;42(suppl 16):e17054. doi:10.1200/JCO.2024.42.16_suppl.e17054

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