The oncologist · 2025
Toxicity-benefit analysis of advanced prostate cancer trials using weighted toxicity scoring.
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Gill Jaspreet K, Sperandio Rubens C, Hoang Tuan, Emmenegger Urban
Аннотация
OBJECTIVE: The weighted toxicity score (WTS) is a metric suitable for comparing the toxicity burden in experimental versus control arms of randomized controlled trials (RCTs). When paired with clinical endpoints, the WTS offers a framework to evaluate the toxicity-benefit profile of anti-cancer agents. This study applied the WTS to phase III advanced prostate cancer (PC) clinical trials.
DESIGN: Select phase III PC RCTs with adverse event (AE) data were compiled. The WTS was calculated for each trial arm using 2 approaches: (1) all AEs (A-WTS) and (2) symptomatic AEs (S-WTS). Percent change in WTS between trial arms quantified the toxicity burden, while hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were used to assess efficacy.
RESULTS: Seventeen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors [ARSi, n = 4], poly (ADP-ribose) polymerase inhibitor monotherapy [PARPi, n = 2], ARSi + PARPi [n = 3], ARSi + ARSi [n = 3], triplet therapy [n = 3], and docetaxel as well as Lutetium-177 (177Lu)-PSMA-617) [n = 1 each]). Overall, toxicity and efficacy were greater among experimental than control arms (median A-WTS 6.62 vs. 4.10; median S-WTS 3.91 vs. 3.08; median HR for OS 0.75, median HR for PFS 0.61). ARSi + PARPi studies observed the highest average A-WTS increase (78%), whereas ARSi + ARSi and triplet therapy trials noted the lowest average A-WTS increases (31% and 32%, respectively) with favorable clinical outcomes.
CONCLUSIONS AND RELEVANCE: RCTs demonstrated increased toxicity in experimental arms relative to controls, with both toxicity and survival outcomes varying across therapeutic strategies.
DESIGN: Select phase III PC RCTs with adverse event (AE) data were compiled. The WTS was calculated for each trial arm using 2 approaches: (1) all AEs (A-WTS) and (2) symptomatic AEs (S-WTS). Percent change in WTS between trial arms quantified the toxicity burden, while hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were used to assess efficacy.
RESULTS: Seventeen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors [ARSi, n = 4], poly (ADP-ribose) polymerase inhibitor monotherapy [PARPi, n = 2], ARSi + PARPi [n = 3], ARSi + ARSi [n = 3], triplet therapy [n = 3], and docetaxel as well as Lutetium-177 (177Lu)-PSMA-617) [n = 1 each]). Overall, toxicity and efficacy were greater among experimental than control arms (median A-WTS 6.62 vs. 4.10; median S-WTS 3.91 vs. 3.08; median HR for OS 0.75, median HR for PFS 0.61). ARSi + PARPi studies observed the highest average A-WTS increase (78%), whereas ARSi + ARSi and triplet therapy trials noted the lowest average A-WTS increases (31% and 32%, respectively) with favorable clinical outcomes.
CONCLUSIONS AND RELEVANCE: RCTs demonstrated increased toxicity in experimental arms relative to controls, with both toxicity and survival outcomes varying across therapeutic strategies.