SAVE: A multicenter randomized phase 2 trial of salvage radiotherapy (SRT) with androgen-deprivation therapy (ADT) versus apalutamide (Apa) for biochemical progression after radical prostatectomy (RP).

364 Background: Adding 6 months of ADT to SRT can negatively impact health-related quality of life (HRQoL). SAVE evaluated apalutamide as an alternative to maintain HRQoL. Methods: SAVE (NCT03899077) is an investigator-initiated, multi-center, open label, randomized phase 2 trial. Patients had a rising PSA after RP and were referred for SRT. Only patients with adequate erectile function (IIEF-5 score ≥ 8) were eligible. Patients were randomized to 6 months of ADT (investigator's choice) or 6 months of Apa. Primary endpoint was the EPIC-26 sexual domain (SD) score at 9 months after starting hormonal treatment (HT) compared between both arms by the Wilcoxon test. The study was powered to detect a 15-points difference between both arms with 90% power and one-sided type I error of 0.05. Secondary endpoints included overall HRQoL, assessed using EPIC-26, FACT-P, EORTC QLQ C30 and PR25, at 3, 6 and 9 months, and PSA response rates (at least 80% decline). Results: 201 participants from 7 sites were randomized from 04/17/2019 to 10/16/2024 to ADT (100) or Apa (101). Pretreatment scores were not significantly different in both arms. Median (Q1 – Q3) EPIC-26 SD score at 9 months after starting HT was significantly higher in the Apa (57 (39 – 79)) than in the ADT (19 (6 – 38)) group (p < 0.001). Similar differences in SD scores were observed at 3 (50 (26 – 71) vs 15 (4 – 32), p < 0.001) and 6 (45 (26 - 71) vs 13 (4 – 28), p < 0.001) months. EPIC-26 urinary incontinence (92 (79 – 100) vs 86 (65 – 100), p = 0.01 at 3 months; 92 (79 – 100) vs 86 (61 – 100), p = 0.056 at 6 months) and hormonal (90 (80 – 95) vs 80 (60 – 90), p < 0.001 at 3 months; 85 (75 – 95) vs 75 (60 – 85), p< 0.001 at 6 months; 95 (85 – 100) vs 80 (65 – 90), p< 0.001 at 9 months) domain scores were better in the Apa arm. FACT-P total score was 126 (112 – 137) vs 119 (109 – 131) at 3 (p = 0.018), 129 (116 – 138) vs 122 (110 – 132) at 6 (p = 0.025), and 133 (126 – 140) vs 128 (117 – 136) at 9 (p = 0.006) months. Significantly better scores were observed with Apa on the physical and functional well-being as well as prostate cancer-specific scales at all timepoints. PR25 showed significantly higher sexual activity and functioning scores as well as less urinary and hormonal treatment related symptoms with Apa at all timepoints. Global health status (C30) was 83 (67 – 83) vs 67 (58 – 83) at 3 (p = 0.011), 83 (67 – 92) vs 67 (58 – 83) at 6 (p < 0.001), and 83 (83 – 100) vs 75 (67 – 83) at 9 (p < 0.001) months. Significantly better physical, role, emotional, cognitive and social functioning, as well as less fatigue was observed with Apa at all timepoints. PSA response rates were similar at 3 (82% with Apa vs 75% with ADT, p = 0.3), 6 (84% vs 73%, p = 0.12) and 9 (76% vs 74%, p = 0.9) months. Conclusions: Apalutamide monotherapy significantly spares HRQoL compared to ADT, not only regarding sexual functioning but also more generally, without jeopardizing PSA response. Clinical trial information: NCT03899077 .