Bone-Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms

Abstract

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.

Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302

“…These associations are consistent with an interaction between abiraterone and BTT use that may benefit clinical outcomes. In fact there is accumulating preclinical and clinical evidence of a potential anticancer effect of bisphosphonates [13]. In a retrospective analysis of a phase 3 clinical trial on zoledronic acid versus placebo, zoledronic acid–mediated normalization of bone markers was associated with improved survival in men with bone metastases from CRPC [28].…”

“…The BTT agents bisphosphonates and denosumab inhibit osteoclast-mediated bone resorption and can prevent bone loss and increase bone mineral density in patients with prostate cancer receiving androgen deprivation therapy [10–12]. Zoledronic acid and denosumab are effective for the prevention of skeletal-related events in patients with metastatic prostate cancer [13]. Historically, bone-seeking radiopharmaceuticals have been used as a palliative treatment for pain in patients with metastatic prostate cancer [14].…”

Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review

“…35 This landmark study led to the US Food and Drug Administration approval of denosumab (commercialized as Prolia) in non-metastatic prostate cancer patients undergoing ADT as the only approved therapy to prevent hormone therapyassociated fractures. 36 Selective estrogen-receptor modulators Selective ER modulators (SERMs) have shown some promising results for BMD preservation in PCa for patients undergoing ADT. Raloxifene was first studied and was associated with an increase in BMD at the total hip and the trochanter (Po0.001) compared with placebo in a 12-month randomized trial of 48 men with non-metastatic PCa undergoing ADT.…”

Palliative treatment of metastatic bone pain with radiopharmaceuticals: A perspective beyond Strontium-89 and Samarium-153

“…Data from these studies showed that there was no evidence of long-term toxicity during the 2-year follow-up and administered activities of at least 50 kBq/kg had a significant positive effect in bone alkaline phosphatase (ALP), prostate-specific antigen (PSA) levels, pain reduction and overall survival (El-Amm et al, 2013;Harrison et al, 2013;Nilsson et al, 2012). In general, 223 RaCl 2 was well tolerated, and no dose-limiting hemotoxicity was observed (Harrison et al, 2013).…”