Abstract
Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords “prostate cancer”, “metastatic castration-resistant prostate cancer”, “DDR pathways”, “ARS inhibitors”, “PARP inhibitors”, “IC inhibitors”, “PSMA-targeting agents”, and “drug combinations” was performed.
Highlights
The androgen receptor (AR) pathway is the key driver for prostate cancer (PCa) growth and subsequent progression.Two potent AR-signaling (ARS) inhibitors, abiraterone acetate and enzalutamide, were first developed in patients with metastatic castration-resistant PCa [1,2], and along with the taxanes docetaxel and cabazitaxel and the alpha emitter radium-223 dichloride represent current best practice in this disease in many Western countries
No significant difference in cause-specific survival (CSS) was observed between carrier patients and non-carriers, except for BRCA2 carriers who showed a significant improvement in CSS
The findings showed that in patients without DNA damage repair (DDR) pathway alterations, there were no significant differences between the two arms in terms of prostate-specific antigen (PSA) response, tumor response, and progression-free survival (PFS), and a fusion gene (ETS) status did not affect the results
Summary
The androgen receptor (AR) pathway is the key driver for PCa growth and subsequent progression. Germline DDR gene mutations occurring most frequently in BRCA2 gene have been associated with more aggressive disease features, a higher risk of relapse, and overall a poor prognosis, independently of prostate-specific antigen (PSA) value and/or cellular differentiation score [3] Along these lines, DDR genes such as ATM, CHEK2, BRCA1, and BRCA2 are largely investigated as putative biomarkers in PCa patients. Specific DDR alterations may favor a high mutational burden, and trigger the expression of specific neoantigens as well as the increase of tumor-infiltrating lymphocytes This could support the role of immunotherapeutics, especially using agents targeting the programmed cell death protein (PD)-1 receptor or its ligand (PD-L1) [9]. Considering all this, for our review, we selected clinical research into mCRPC patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors, in an attempt to formulate evolving treatment paradigms in this disease phase
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