Bone-targeted therapies to reduce skeletal morbidity in prostate cancer

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents

The new era of prostate-specific membrane antigen-directed immunotherapies and beyond in advanced prostate cancer: a review

The lack of success in prostate cancer from immune checkpoint inhibitors, which is likely multifactorial, has led to the development and investigation of a number of other novel immunotherapeutic techniques, including antibody–drug conjugates, T-cell redirected bispecific therapies, cancer vaccines and chimeric antigen receptor T-cell therapies. Prostate-specific membrane antigen (PSMA) is a tumour-associated antigen (TAA) that is highly expressed in metastatic prostate cancer and has been validated as an effective target for radionuclide treatment. But while PSMA has thus far been the ‘front runner’ target for these novel immunotherapeutic techniques, it may not be the ideal target for immunotherapy and there are other potential targetable TAAs that will require further exploration. This review will focus on these various PSMA-directed therapies, as well as other potential targets for immunotherapy beyond PSMA

Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials