Prostate cancer ranks as the second most prevalent cancer and the fifth leading cause of cancer-related deaths in men globally. Despite several treatment options, tumors can turn resistant against therapy, leaving a high unmet medical need for patients. Recently published in Clinical Cancer Research, researchers from Bayer in collaboration with Minerva Imaging unveiled preclinical efficacy of a PSMA-targeted alpha therapy, presenting a promising avenue for improved patient outcomes.

Prostate cancer treatment

The study delved into both the in vitro properties and in vivo characteristics of 225Ac-macropa-pelgifatamab (225Ac-pelgi ) alongside other alpha therapies. Biodistribution, antitumor effectiveness, and tolerability was investigated in mouse prostate cancer xenograft models derived from both cell lines and patients. Additionally, the study explored how the anti-tumor efficacy of this therapy was affected when used in combination with the androgen receptor inhibitor darolutamide.

Preclinical models

225Ac-pelgi shows robust anti-tumor efficacy in several preclinical mouse models including C4-2, LNCaP (See Figure 1), and KUCaP-1. Profound anti-tumor effects were observed as evidenced by significant inhibition of tumor growth and extended survival rates. The treatment exhibited a favorable safety profile, suggesting its potential for clinical use.

Growth curves of LNCaP prostate cancer model.

Figure 1: Growth curves of LNCaP tumors in mice treated with vehicle or 70, 125, or 250 kBq/kg 225Ac-pelgi. From Schatz et all, Clinical Cancer Research 2024.

Efficacy and biodistribution

Androgen receptor inhibitors have a dual effect increasing PSMA levels while decreasing DNA repair gene expression. This dual action hampers DNA repair mechanisms and sensitizes cancer cells to radiation, offering a strong rationale for combining PSMA-targeted therapies with androgen receptor inhibitors like darolutamide to potentially amplify treatment effectiveness. The study demonstrated that the combination of 225Ac-pelgi and darolutamide enhanced the efficacy over respective monotherapies in the ST1273 prostate patient-derived xenograft (PDX) model (See figure 2). Moreover, in the 22Rv1 CDX model characterized by PSMA expression but androgen independence, the combination treatment outperformed 225Ac-pelgi monotherapy. Notably, darolutamide alone did not exhibit efficacy. Throughout the study all treatments were well tolerated, indicated by stable body weights.

Growth curves of ST1273 prostate cancer PDX model.

Figure 2: Growth curves of ST1273 tumors in mice treated with vehicle, 225Ac-pelgi, darolutamide, or combination. From Schatz et all, Clinical Cancer Research 2024

The biodistribution studies showed that 225Ac-pelgi was rapidly cleared from the circulation blood and accumulated in the tumors with a significant concentration of the compound remaining in the tumor for up to 3 weeks post-dosing.

A phase 1 clinical trial is currently ongoing to evaluate the safety, tolerability, pharmacokinetics, and antitumor efficacy of 225Ac-pelgi. The preclinical data of the PSMA-targeted alpha therapy shows promising results and represents a significant stride forward in the fight against advanced prostate cancer.

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