Original Research Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised clinical TITAN study

Background: Whether disease burden in patients with metastatic castration -sensi-tive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalu-tamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation. Methods: These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and >= 1 bone metastases or >= 4 bone lesions with >= 1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (<= 5 bone-only metas-tases) or polymetastases (>5 in bone +/- other locations or <= 5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate -specific antigen progression or castration resistance were assessed using Cox proportional hazards models.Results: Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchro-nous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53-0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40-1.05]; p = 0.08), meta-chronous/high-volume (0.69 [0.33-1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09-0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligome-tastatic disease.Conclusion: TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, sup-porting early apalutamide intensification in mCSPC.Clinical Trial Registration: NCT02489318.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).