Initial report of a randomized trial of post-prostatectomy prostate cancer radiotherapy using either fluciclovine ( <sup>18</sup> F) or PSMA ( <sup>68</sup> Ga) PET/CT for target dose-escalation.
Authors: Ashesh B. Jani, Vishal Ramesh Dhere, Subir Goyal, Eduard Schreibmann, Pretesh R. Patel, Bruce Warren Hershatter, Joseph W. Shelton, Sheela Hanasoge, Nikhil Sebastian, Sagar Anil Patel, Raghuveer Halkar, Bridget Fielder, Olayinka A. Abiodun-Ojo, Ismaheel Lawal, Aliza Mushtaq, Viraj A. Master, Shreyas Joshi, Omer Kucuk, Mehmet Asim Bilen, David M. Schuster
Journal: Journal of Clinical Oncology (2025)

326 Background: Fluciclovine PET-guided prostate cancer (PCa) radiotherapy (XRT) improves failure-free survival (FFS) over conventional imaging (CI) alone in post-prostatectomy (RRP) recurrence (EMPIRE-1, PMID: 33971152). In this randomized trial we explored dose-escalation (DE) to sites of PET uptake (not done in EMPIRE-1) using either fluciclovine or 68 GaPSMA PET/CT-guided XRT and compared cancer control to the fluciclovine PET arm of EMPIRE-1 2Y failure free survival (FFS) of 79.6%. Methods: From 2019-2023, 140 pts w/ PCa with detectable PSA post-RRP &amp; negative CI were stratified by: (a) PSA (&lt;1.0 v ≥ 1.0 ng/mL), (b) adverse path [+ECE, +SV, +margin, +node] (0 v any) &amp; (c) ADT (Y v N) &amp; randomized to XRT directed by fluciclovine (Arm 1) v 68 GaPSMA (Arm 2). In both Arms, XRT decisions were PET determined: (A) extrapelvic (EP) uptake (no XRT); (B) pelvic uptake (XRT to pelvis + prostate bed [PB]); (C) PB only uptake (XRT to PB); &amp; (D) no uptake (XRT to PB). Pelvic dose: 45.0-50.4/1.8 Gy (with optional DE {to PET uptake} up to 56 Gy); PB dose: 64.8-70.2 Gy (with optional DE up to 76 Gy). Failure was defined as in EMPIRE-1. Primary endpoint, declared a priori, was 2Y FFS comparing entire cohort [Arms (1+2)] to the 79.6% 2Y FFS of the fluciclovine PET arm of EMPIRE-1 using Z-test. KM curves for Arms 1 &amp; 2 were compared using log-rank test. Univariate (UV) &amp; multivariable (MV) analyses were performed by Cox proportional hazards model on demographic, disease, &amp; treatment factors. Provider-reported [acute &amp; late, GI &amp; GU] toxicities were compared using χ 2 test. Results: 140 pts were enrolled (Arm 1: 70; Arm 2: 70). Arms were balanced on age, race, PSA, GG, ECE, SV, margin, node, &amp; ADT use. 5 pts in Arm 1 and 1 pt in Arm 2 withdrew before PET. For pts completing XRT (Arm 1: 59; Arm 2: 60), median FU was 2.00 years. For primary endpoint, 2Y FFS for Arm (1+2) 87.4 v 79.6% target from EMPIRE-1 (p=0.018). There were no significant differences in 2Y FFS between Arm 1 v Arm 2 (88.2% v 86.9%, p=0.604). PET uptake in Arms 1 v 2 were: EP: 5 v 8; pelvic+/-PB: 10 v 10; PB only: 47 v 24; none: 3 v 27. Typical PB DE (n=74) was 74 Gy &amp; pelvis DE (n= 16) was 55 Gy. For Arm 1 v Arm 2, covariates reaching p &lt;0.10 on UV analysis were: +SV (p=0.010), +margin (p=0.039), PB uptake (p=0.068), &amp; PB boost (p=0.085), and on MV analyses were: +SV (p=0.004), ADT (p=0.067), +margin (p=0.069), &amp; PB boost (p=0.096). Toxicity was similar &amp; low in both Arms 1 &amp; 2. Conclusions: Although fluciclovine had higher diagnostic yield in the PB &amp; 68 GaPSMA had higher yield for EP disease, both radiotracers had similar yield in the pelvic LN, &amp; both radiotracers had similar impact on FFS in this setting. Integrating either fluciclovine or 68 GaPSMA into post-RRP XRT planning for DE to sites of PET uptake in PB or pelvis resulted in improved FFS over a prior trial in which no DE was performed; other factors may also have contributed to this observed difference. Clinical trial information: NCT03762759 .