The Role of Theranostics in Prostate Cancer

Abstract

Theranostics in men with metastatic castration-resistant prostate cancer (mCRPC) has been developed to target bone and the tumor itself. Currently, bone-directed targeted alpha therapy with radium-223 (²²³Ra) is the only theranostic agent proven to prolong survival in men with mCRPC who have symptomatic bone metastases and no known visceral metastases. The clinical utility and therapeutic success of ²²³Ra has encouraged the development of other tumor-targeting theranostic agents in mCRPC, primarily targeting prostate-specific membrane antigen (PSMA) with radioligand therapy (RLT). There is increasing evidence of promising response rates and a low toxicity profile with ¹⁷⁷Lu-labeled PSMA RLT in patients with mCRPC. A phase III randomized study of ¹⁷⁷Lu-labeled PSMA RLT has completed accrual and is awaiting results as to whether the drug improves radiographic progression-free survival and overall survival in men with mCRPC receiving standard of care treatments. Additional early clinical trials are investigating the role of tumor-directed targeted alpha therapy with radiotracers such as ²²⁵Ac. In this article, we review the current status of theranostics in prostate cancer, discussing the challenges and opportunities of combination therapies with more conventional agents such as androgen receptor inhibitors, cytotoxic chemotherapy, and immunotherapy.

Figure

(A) Mechanism of action of radium-223 (²²³Ra). ²²³Ra substitutes for calcium in hydroxyapatite complexes in woven bone surrounding prostate cancer metastatic lesions. ²²³Ra emits high-energy alpha particles over a range of ≤100 μm. The alpha radiation leads to localized cytotoxicity through the induction of DNA double-strand breaks in adjacent tumor cells, osteoblasts and osteoclasts, which disrupts the positive-feedback loops between these cells, leading to inhibition of tumor growth and pathological bone reaction and stabilization of the normal bone microenvironment. (B) Disease-specific theranostic agents, many being used in combination with other anticancer agents targeting distant metastatic disease, are in being used in routine clinical practice or are under preclinical or clinical investigation in mCRPC.