Optimizing the management of castration‐resistant prostate cancer patients: A practical guide for clinicians

Abstract

Background Advanced prostate cancer (PC) patients, especially those with metastatic prostate cancer (mPC), often require complex management pathways. Despite the publication of clinical practice guidelines by leading urological and oncological organizations that provide a substantial and comprehensive framework, there are numerous clinical scenarios that are not always addressed, especially as new treatments become available, new imaging modalities are developed, and advances in genetic testing continue. Methods A 14‐member expert review panel comprised of urologists and medical oncologists were chosen to provide guidance on addressing specific topics and issues regarding metastatic castration‐resistant prostate cancer (mCRPC) patients. Panel members were chosen based upon their experience and expertise in the management of PC patients. Four academic members (two urologists and two medical oncologists) of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association (LUGPA) practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, each assigned a specific mCRPC topic to review and discuss with the entire panel. Results This article describes the practical recommendations of an expert panel on the management of mCRPC patients. The target reading audience for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. Conclusion The panel has provided recommendations for managing mCRPC with regard to specific issues: (a) biomarker monitoring and the role of genetic and molecular testing; (b) rationale, current strategies, and optimal sequencing of the various approved therapies, including hormonal therapy, cytotoxic chemotherapy, radiopharmaceuticals and immunotherapy; (c) adverse event management and monitoring; and (d) imaging advanced PC patients. These recommendations seek to complement national guidelines, not replace them, and a discussion of where the panel agreed or disagreed with national guidelines is included.

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

“…Immunotherapy, such as sipuleucel-T or immune checkpoint inhibitors (nivolumab and pembrolizumab, binding and inactivating the T cell antigen PD1; durvalumab, targeting PD-L1), is another therapeutic strategy for CRPC patients. Unfortunately, serious side effects and a lower efficacy than expected are commonly associated with chemotherapy and immunotherapy, respectively [ 253 , 254 , 255 , 256 , 257 ].…”

“…Given the persisting role of the AR in the progression of PCa to the CRPC stage, inhibitors of the androgen pathways are commonly used for the treatment of CRPC patients [ 38 , 254 , 255 , 257 , 258 ]. Second-generation non-steroidal AR antagonists (enzalutamide, apalutamide, darolutamide) compete with androgens by binding to AR receptors and also inhibit AR translocation into the nucleus and its downstream binding to, and activation of, response elements in the promoter region of specific target genes.…”

“…Abiraterone, the inhibitor of CYP17A1 activity and, therefore, of androgen biosynthesis, demonstrated efficacy (reduction of risk of death, PFS and OS) and safety in metastatic CRPC patients, both in the pre- and post-chemotherapy settings [ 266 , 267 , 268 ]. Interestingly, it has been observed that, in a sequential treatment setting, starting therapy with abiraterone and subsequently switching to enzalutamide provides better results (in terms of PFS and PSA-PFS) than those obtained with the opposite sequence [ 39 , 255 , 257 , 269 ].…”

“…In accordance with these observations, ADT interventions, based on a gonadotropin-releasing hormone agonist, with or without an antiandrogen drug (AR antagonist or inhibitor of androgen synthesis), represent a mainstay treatment for PCa, even in the CRPC stage [ 255 , 257 , 258 ]. Recent clinical trials (PROSPER, SPARTAN, ARAMIS) reported a synergistic positive effect of AR antagonists (enzalutamide, apalutamide, darolutamide) and GnRH analog-based ADT on clinical outcomes (PSA levels and doubling time, median time to metastasis, PFS, OS, risk of death) in non-metastatic CRPC patients [ 262 , 293 , 294 , 295 , 296 ].…”

“…Results from these trials demonstrate that “initiating therapy at early stage of the disease is more effective than waiting until mCRPC development” [ 38 ]. The optimal sequencing and combination of these standard treatment strategies for CRPC patients is still a matter of debate [ 255 , 257 ].…”