GRPR-Targeted Radioligand Therapy in Prostate Cancer: The A9-0631 and A9-0642 Trial

A new first-in-human study is testing whether GRPR-targeted radiopharmaceuticals can extend precision oncology beyond the PSMA and SSTR frameworks. The trial combines two therapeutic agents, 177Lu-A9-0631 and 225Ac-A9-0642, with GRPR imaging using 68Ga-A9-6217 or low-dose 177Lu-A9-0631 in patients with GRPR-positive solid tumors.

GRPR, or gastrin-releasing peptide receptor, is an appealing target because it is overexpressed in several cancers, including prostate, breast, and colorectal tumors. That makes it useful both for imaging and for therapy: the same receptor can guide a radioactive compound to the tumor and then deliver radiation directly to cancer cells.

The study is a phase 1–1b multicenter, open-label trial designed to evaluate safety, dosimetry, and early efficacy in adults with locally advanced, unresectable, or metastatic GRPR-positive solid tumors. The main disease groups include prostate cancer, HR+/HER2- breast cancer, colorectal cancer, and other GRPR-positive malignancies.

Two therapeutic radionuclides are being explored. Lutetium-177 is a beta emitter and is widely used in radioligand therapy because it can treat tumors while keeping normal tissue exposure relatively controlled. Actinium-225 is an alpha emitter, which can deliver very intense radiation over a very short range and may be especially powerful against resistant disease.

The imaging component uses 68Ga-A9-6217 to identify GRPR expression and help select patients. Low-dose 177Lu-A9-0631 can also be used for imaging and dosimetry, which is crucial in a program designed to estimate absorbed dose in both tumors and healthy organs.

The trial begins with dose escalation to determine the maximum tolerated dose and recommended phase 2 dose for both therapeutic agents while collecting safety and dosimetry data. It then moves into dose expansion, where more patients are treated at the chosen dose to better understand tolerability and get an early signal of antitumor activity.

What makes the program notable is that it is a full theranostic platform rather than a single-agent study. It pairs diagnostic imaging with both beta- and alpha-emitting treatment options, which gives researchers a chance to compare two different radiation strategies within the same receptor target.

The field is paying attention because GRPR could become a useful complement to PSMA-based imaging and therapy, especially in tumors or lesions that do not express PSMA strongly.

Clinical trial.