Mortality risk with androgen receptor pathway inhibitors: Real-world evidence.

64 Background: Androgen deprivation therapy (ADT) is the standard of care in advanced prostate cancer (PCa). In recent years, androgen receptor pathway inhibitors (ARPIs) have been introduced as important additions to ADT to further suppress androgen signaling and improve oncologic outcomes, and ADT+ARPI treatment is now guideline-recommended standard of care. While ARPIs prolong cancer survival, accumulating evidence reinforces longstanding concerns that they may exacerbate cardiovascular (CV) risk; a recent systematic review (n=22,000) demonstrated that addition of ARPIs to ADT was associated with approximately a 2x increase in the risk of all-grade CV events (RR 1.75) and grade ≥3 CV events (RR 2.10). Since CV events contribute significantly to mortality in this population, survival outcomes are of particular concern. Using real-world data, the objective of this study was to evaluate the risk of all-cause mortality (ACM) after ADT initiation for patients treated with ADT+ARPI vs. ADT without an ARPI. Methods: Data were collected from the Decision Resources Group (DRG, now Clarivate) Real World Evidence repository, including >300 million patients' medical and pharmacy claims and EHR data. The analysis set included PCa patients who received ≥ 1 ADT injection (99% of patients started ADT within 2010-2020). Kaplan-Meier survival curves were constructed, and Cox regression was used to compare ACM rates between patients on ADT+ARPI vs. ADT without ARPI. Results: 44,439 men with PCa were included in the analysis. At 4 years after ADT initiation, ACM risk was higher for patients with ARPI vs. without (25.1% vs 14.4% for the ARPI vs without ARPI groups, respectively). The unadjusted HR was 1.82 (95% CI 1.73-1.91, p<0.001), indicating a statistically significant difference consistent with the KM curve. After adjustment, the adjusted HR for ACM risk in ARPI vs. without ARPI patients remained significant at 1.60 (95% CI 1.37-1.86, p<0.001). Conclusions: While doublet therapy is guideline-recommended standard of care for PCa, addition of ARPI therapy to foundational ADT is associated with a significantly increased mortality risk in PCa patients compared to ADT without ARPI. Extending findings of a prior systematic review of clinical trial data that showed increased CV risk with ARPIs, our real-world analysis of ~45,000 patients also demonstrates an associated increase in ACM risk. This is notable as ARPIs are intended to prolong survival, underscoring the need to proactively assess and manage mortality risk in patients on ADT, particularly when combining ADT with an ARPI. Clinicians should assess baseline CV risk and comorbidities that exacerbate CV disease when initiating ARPI-based doublet therapy and, based on prior real-world analyses (Crawford et al., J Urol, 2024), consider preferential use of LHRH agonists over GnRH antagonists in appropriate patients.