SUO 2018: Uptake on PSMA Targeted Alpha Emitters in mCRPC

Phoenix, Arizona ( Prostate-specific membrane antigen (PSMA), a cell surface enzyme, has high and consistent expression in metastatic prostate cancer (PCa) and relatively low or no expression in normal prostate cells. Furthermore, it has been established that attenuated androgen receptor (AR) signaling is a hallmark of lethal prostate cancer, and AR signaling pathway activity is inversely related to PSMA expression. Therefore, PSMA has consequently become a target of interest for targeted radioligand therapy, especially in metastatic castrate-resistant prostate cancer (mCRPC).

Radiation remains a common treatment for PCa in the curative and palliative settings, and radiolabeled targeted therapy is increasingly studied. Radiolabeled β-DOTA-J591 has been found to have accurate targeting in 89%, a dose response, clearance of circulating tumor cells, predictable clinical response with reversible myelosuppression and the ability to give subsequent chemotherapy. There are differences between monoclonal antibodies (mAb) and small molecule ligands in terms of targeted radiotherapy. Monoclonal antibodies are large, have a long circulation time, are largely targeted through the bloodstream, and are associated with bone marrow and liver toxicities. Small molecule ligands are small, have a short circulation time, rapidly diffuse to all sites of expression, and are associated with kidney, salivary glands, and small bowel toxicities.

Prospective randomized control trials evaluating PSMA-β targeted radiotherapy. Alpha ionizing radiation has a 4,000-fold higher energy but travels short distances and is blocked by thin barriers such as the skin. Beta has lower energy, but can travel through barriers such as skin, stopping within an inch of tissue. Recent publications evaluated Ac-PSMA-617 in terms of dosimetry and efficacy including the known toxicity of xerostomia which is the dose-limiting side effect. The South African group has found that all patients had xerostomia and 1 patient had grade 4 renal failure. Dose escalation studies are underway for numerous targeted radiotherapy ligands including Ac-J591 and BAY 2315497 (phase 1 clinical trial recently announced.

In summary, PSMA is a clinically validated, consistent, cell surface target particularly in CRPC and remains relevant in the current era. Antibodies and small molecule ligands accurately target PSMA+ cells and can be radiolabeled, and because prostate cancer is radiosensitive, alpha emitters can be quite potent. Given the selectivity of PSMA, particularly in metastatic Pca, therapy can be targeted with relative sparing of normal organs. One question from the panel was regarding the approach to treatment for PSMA cold lesions; for these tumors, improved understanding through study of biology and molecular pathways, and combination therapies will be important.

Presented By: Scott Tagawa, MD, Weill Cornell Medical College

Written by: Selma Masic, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, @selmasic, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona