Real-world data from the VA suggests abiraterone is associated with increased hospitalizations for cardiovascular events, infections, and acute kidney injury compared to other ARPIs. This finding prompts clinicians to favor AR antagonists like enzalutamide in older, comorbid patients at higher risk for these complications.

A meta-analysis of six trials (Poseidon) found no overall survival benefit from adding long-course (24 months) hormone therapy to post-operative radiotherapy. It suggests that a shorter course of 4-6 months is adequate for most men, marking a significant shift towards treatment de-escalation to reduce long-term toxicity without compromising efficacy in this specific setting.

Androgen deprivation therapy induces metabolic syndrome-like effects, increasing cardiovascular risk. It is the medical oncologist's responsibility to perform a baseline CV risk assessment using tools like the STAMP questions and to engage cardiology partners when needed for risk mitigation.

ADT monotherapy is an obsolete strategy for metastatic prostate cancer. For patients too frail for standard ADT+ARPI combination therapy, enzalutamide monotherapy is a superior alternative. It offers effective treatment that can be quickly stopped to reverse side effects if tolerance issues arise, unlike injectable ADT.

The PRESTO trial evaluated adding apalutamide (APA) and abiraterone (Abby) to a standard LHRH analog. The triplet combination arm demonstrated increased toxicity without any additional efficacy gains compared to the doublet arm (LHRH + APA). This finding reinforces that more intensive combination therapy is not always better and can be detrimental in this setting.

Though cross-trial comparisons are imperfect, Grade 3+ anemia rates offer a stark contrast between approved PARP+ARPI combinations. The rate was 16% for olaparib+abiraterone (PROPEL) versus a much higher 49% for talazoparib+enzalutamide (TALAPRO-2). This suggests toxicity profiles should be a key factor in treatment selection.

Clinical trials combining potent ARPIs like abiraterone and enzalutamide have consistently failed. Once the androgen receptor pathway is maximally suppressed by one agent, adding another with a similar mechanism provides no further clinical advantage, much like hammering a nail that is already flush with the wood.

A VA study using real-world data confirms that androgen receptor pathway inhibitors (ARPIs) combined with ADT significantly improve survival in elderly (>75), frail, and high-comorbidity prostate cancer patients. This evidence directly addresses clinician hesitancy to treat these vulnerable populations with standard-of-care combination therapy.

Registrational clinical trials for prostate cancer drugs enroll patients who are substantially younger (median age 67-69) and healthier than the typical real-world patient (median age 73-74). This gap means trial data on efficacy and safety doesn't perfectly apply to the majority of patients seen in clinic.