Combining Prostate Cancer Radiotherapy with Therapies Targeting the Androgen Receptor Axis

Abstract

Background Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or recurrent pca, management typically includes the combination of long-term androgen deprivation therapy (adt) and radiotherapy (rt). New androgen-receptor-axis targeted therapies (arats), which await validation, offer an option to intensify therapy.Methods In this narrative review, we report the relevant history that has supported combining adt with rt. The literature in PubMed was searched for studies involving pca and novel arats (abiraterone acetate, enzalutamide, apalutamide, darolutamide) published between 1995 and 2019. Literature discussing clinical trials in which those modalities were combined was extracted and synthesized into a combined molecular and clinical discussion. Potential treatment intensification mechanisms and rationales are explored.Results Early results from three phase i/ii trials demonstrated that concurrent abiraterone acetate, adt, and rt is safe, improves the extent of chemical castration, and is associated with limited treatment failures. A single in vitro study implies synergy for radiosensitization beyond that facilitated by conventional adt. Studies investigating the combination of other arats with rt are under way, including multiple phase iii trials, but short-term results are not yet available.

Targeting the radiation-induced ARv7-mediated circNHS/miR-512-5p/XRCC5 signaling with Quercetin increases prostate cancer radiosensitivity

“…We and some groups have demonstrated that AR expression and activity are upregulated following IR in PCa models and AR can activate DDR pathways [4,5,10,39,40] in PCa, providing rationale for concurrent ADT + RT therapy [6,41] as being better than RT therapy alone. These preclinical studies also have led to testing combinations of RT with next generation hormonal agents such as abiraterone, Enz, apalutamide and AR degradation enhancer, ASC-J9 [40,[42][43][44][45]. However, despite use of combined ADT and RT, the recurrence rate is up to 50% in high-risk PCa patients [6].…”

A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer

“…Our findings support using a lead-in design for nonhormonal novel agents combined with RT and ADT, especially when an early phase combination is administered with curative intent. Moreover, androgen–receptor-axis targeted drugs combined with RT and ADT are under investigation, 19 and the results are highly anticipated.…”

Targeting the Radiation-Induced ARv7-Mediated circNHS/miR-512-5p/XRCC5 Signaling With Quercetin Signaling Increases Prostate Cancer Radiosensitivity

“…We and some groups have demonstrated that AR expression and activity are durably upregulated following IR in PCa models and AR can activate DDR pathways (4,5,10,39,40) in PCa, providing rationale for concurrent ADT + RT therapy (6, 41) is better than RT therapy alone. These preclinical studies also have led to testing combinations of RT with second-generation antiandrogens such as abiraterone, enzalutamide, apalutamide and AR degradation enhancer, ASC-J9 (40,(42)(43)(44)(45). However, despite use of combined ADT and RT, the recurrence rate is up to 50% of high-risk PCa patients (6).…”