Combination therapy in metastatic hormone-sensitive prostate cancer: is three a crowd?

Abstract

The mainstay of treatment for metastatic prostate cancer is androgen deprivation therapy (ADT). Outcomes with ADT are variable but control of hormone-sensitive prostate cancer (HSPC) can often be achieved for many years. Death from prostate cancer is usually due to the development of escape variants able to survive and proliferate in the setting of castrate levels of serum androgens (metastatic castration-resistant prostate cancer, mCRPC). Several agents can improve survival for patients with mCRPC, including chemotherapy, agents to reduce androgen receptor signalling, the radioisotope radium-223 dichloride, and cellular immunotherapy with sipuleucel-T. Some of these agents have been moved earlier in the disease course and have shown to improve survival in metastatic HSPC also, often to a much greater degree than when the same agents are used in mCRPC. Specifically, survival of metastatic HSPC can be improved with the addition to ADT of any one of docetaxel, abiraterone acetate/prednisone combination, apalutamide, enzalutamide, or darolutamide in combination with docetaxel. Factors affecting outcomes include the volume or burden of disease, timing of metastases relative to the original diagnosis, and patient factors determining the appropriateness of therapy. Unfortunately, uptake of this information by the clinical community remains suboptimal, with many men potentially suitable for combination therapy still receiving only ADT. Some trials have examined the effects of ‘triplet’ therapies although few were designed specifically to address this question. The best evidence to date suggests that triplet therapy with ADT + abiraterone + docetaxel or ADT + darolutamide + docetaxel, can improve overall survival in metastatic HSPC. Clear opportunities exist to improve survival outcomes for men with metastatic HSPC but need to be balanced against cost, accessibility, toxicity, and patient-specific factors.

Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC)—A Potential New Standard of Care

“…As summarized in Table 1 , the management of mCSPC has undergone a paradigm shift in the past decade. Several life-prolonging therapies that have been previously used in the mCRPC setting are now showing prolonged OS benefits when used in the earlier mCSPC setting [ 9 ]. In mCSPC, docetaxel was the first systemic therapy to show an improvement in OS when added to ADT.…”

“…This is likely due to several reasons. mCSPC likely has more favorable disease biology, less acquired treatment resistance, and therefore demonstrates more durable treatment responses [ 9 ]. For example, long-term follow-up of the CHAARTED trial showed a sustained OS benefit with docetaxel (particularly for those with high-volume disease with 8-year OS of 28.5 vs. 15.4%) and a visible tail on the curve suggesting a long-term response in a subset of patients [ 29 ].…”

Triple therapy in metastatic hormone-sensitive prostate cancer

“…Only a few patients have been treated using a sequential approach in all the trials and it is still unclear whether sequencing is better than concurrent treatment [26]. Also, concomitant administration of enzalutamideþD is not recommended because of potential drug interactions and added toxicity, as seen in ENZAMET [7], but the use of triplet therapy sequentially in all patients or in risk-adapted settings based on early responses to ADTþD has not been properly investigated in any studies [5,21 & ]. Secondly, because of the small number of patients with metachronous high-volume nodal disease involved in these trials, it is presently uncertain if this cohort can also benefit from triple therapy.…”

Assessment of androgen receptor signaling inhibitors therapy in metastatic hormone-sensitive prostate cancer

“…Interestingly, the evidence of ARSI is increasingly regarding as effective and safe for mHSPC 4,11 . Abiraterone acetate, the first generation of ARSIs, is a potently selective inhibitor cytochrome P-450 c17 (CYP17), constituting the most important key enzyme for testicular and extragonadal androgen biosynthesis [12][13] . Likewise, the second generation ARSI (enzalutamide, apalutamide and darolutamide) is a potent androgen receptor (AR) inhibitor 13 .…”

“…Abiraterone acetate, the first generation of ARSIs, is a potently selective inhibitor cytochrome P-450 c17 (CYP17), constituting the most important key enzyme for testicular and extragonadal androgen biosynthesis [12][13] . Likewise, the second generation ARSI (enzalutamide, apalutamide and darolutamide) is a potent androgen receptor (AR) inhibitor 13 . The mechanism of actions includes competitive binding to AR, inhibiting androgen receptor nuclear translocation and androgen-receptors-mediated DNA binding 14 .…”