The Musculo-Skeletal Effects of Systemic Anti-Cancer Therapies Combined with Standard Androgen Deprivation in High Risk Localised and Metastatic Hormone Sensitive Prostate Cancer

Abstract

Introduction: Androgen deprivation therapy (ADT) is the mainstay systemic treatment for men with high-risk non-metastaic (M0) and metastatic (M1) prostate cancer leading to bone density loss and increased fracture risk. Treatment intensification with docetaxel chemotherapy, prostate radiotherapy (M1 low volume) and/or androgen receptor signalling inhibitors has demonstrated improved overall survival, but the impact on fracture risk is not known. Healthcare systems data (HSD) through Hospital Episode Statistics permits long-term evaluation of fracture risk beyond standard trial follow up for STAMPEDE trial participants in England. Methods: Linked HSD were analysed for eligible participants recruited to the zoledronic acid, docetaxel, abiraterone +/- enzalutamide, and prostate radiotherapy trials within the STAMPEDE platform. Fracture events were identified using a prespecified coding framework and analysed using competing risk survival models to estimate the impact of each treatment on the cumulative incidence of fracture and calculation of subdistribution hazard ratios (SDHR). Performance of fracture risk estimation at baseline using FRAX was assessed in these cohorts. Exploratory analysis was conducted to assess the potential prognostic value of skeletal muscle area (SMA) and other body composition metrics derived from baseline CT scans. Results: Zoledronic acid significantly reduced fracture risk in M1 participants (SDHR 0.73, 95% CI 0.55-0.97; p=0.015) but not M0 participants. The addition of abiraterone acetate with prednisolone (AAP) +/- enzalutamide significantly reduced fracture risk in M1 (AAP: SDHR 0.77, 95% CI 0.59-0.99, p=0.044; AAP+enzalutamide: SDHR 0.69, 95% CI 0.54-0.88, p=0.002), with no evidence of an effect in M0. There was no evidence of an effect with the addition of docetaxel (M0 and M1) or prostate radiotherapy (M1 only). Baseline FRAX performed poorly across all patient cohorts, with gross underestimation of the actual fracture risk. SMA derived from baseline staging CT scans in M1 patients is a potential prognostic marker for overall survival independent of metastatic disease volume. Conclusions: The cumulative incidence of fracture is high in both M0 and M1 prostate cancer patients. The addition of zoledronic acid or AAP+/-enzalutamide to ADT significantly reduced the risk of fracture in M1 patients with no evidence of effect in M0. These data support the use of bone modifying agents to reduce fracture risk in men with metastatic prostate cancer .

Date of Award	31 Dec 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Michael Brown (Supervisor), Noel Clarke (Supervisor) & Ashwin Sachdeva (Supervisor)