Interaction of age and benefit of treatment intensification in advanced prostate cancer: An aggregate meta-analysis of 14 randomized trials.
Authors: Morgans Alicia K. , Roy Soumyajit , Barata Pedro C. , Brown Jason R , Jia Angela , Zaorsky Nicholas George , Rao Santosh , Mendiratta Prateek , Armstrong Andrew J. , Sweeney Christopher , Attard Gert , James Nicholas D. , Fizazi Karim , Sun Yilun , Spratt Daniel Eidelberg 
Published: January 2024

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Background: Treatment intensification (TI) for men with advanced prostate cancer consistently demonstrates improvements in overall survival (OS) when compared to androgen deprivation therapy (ADT) alone. However, TI increases morbidity and may contribute to worsening other-cause mortality. Herein, we aim to determine if there is an interaction of age and TI on OS in men with advanced prostate cancer. Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings were searched to identify contemporary randomized phase 3 trials in advanced prostate cancer evaluating the role of TI with chemotherapy and/or androgen receptor-signaling inhibition (ARSI) between 1/1/2010-9/1/2023. Trials in metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were included given potential for competing risks; mCRPC trials were excluded. Meta-analyses were performed with random-effect modeling. Meta-regression was performed using Hartung-Knapp methods in mHSPC trials accounting for drug (docetaxel, abiraterone acetate/prednisone (AAP), non-AAP ARSIs (apalutamide, enzalutamide, or darolutamide)), use of RT to primary, percent high volume disease, percent synchronous metastatic disease, and median PSA. Age was dichotomized as < or ≥ 70 in 8 trials, and < or ≥ 65 in 6 trials. Results: Fourteen trials with 16 randomized comparisons (n=17,765 patients) were included. A total of 9,229 younger and 7,458 older men were included in age-specific analyses. Overall, TI significantly improved OS (HR 0.72, 95%CI 0.69-0.76, p<0.0001), which was consistent irrespective of disease state (mHSPC HR 0.72, 95%CI 0.78-0.77; nmCRPC HR 0.74, 95%CI 0.66-0.83). There was a significant interaction between age and TI on OS (p-interaction <0.001); TI in younger men significantly improved OS (HR 0.65, 95%CI 0.59-0.72, p<0.0001). Older men derived less benefit from TI, but TI did improve OS (HR 0.80, 95%CI 0.74-0.87, p<0001). In subgroup of older men in mHSPC trials, a significant treatment effect difference based on drug class was observed (p=0.047); AAP (HR 0.92, 95%CI 0.78-1.10, p=0.38), docetaxel (HR 0.86, 95%CI 0.70-1.05, p=0.13), and non-AAP ARSIs (HR 0.71, 95%CI 0.63-0.81, p<0.001). On meta-regression of mHSPC trials, age remained an independent variable associated with TI benefit (p=0.005). Limitations include the post-hoc nature of this aggregate meta-analysis and use of dichotomized age. Conclusions: TI improves OS for men with mHSPC and nmCRPC, but a significant interaction between age and TI on OS was identified. Further work leveraging individual patient data is needed to understand drivers of this observation, including impact of treatment compliance, comorbid conditions, adrenal suppression, outcomes in different prognostic groups, and competing risks in older patients.