Hearn, Jason W.D.

387 Background: Level 1 evidence supports treatment of high-risk and node positive PCa using 4-9 weeks of radiotherapy (RT) combined with 18-36 months of androgen deprivation therapy (ADT) with or without abiraterone acetate plus prednisone (AAP). While effective, some cancers recur, and this prolonged treatment is associated with inconvenience and variable morbidity. We aimed to determine whether the biological synergy of stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT, AAP, and the PARP inhibitor niraparib, could enable a shorter intensified, yet safe and effective, therapeutic alternative. Methods: ASCLEPIuS (NCT04194554) is a multicenter investigator-initiated phase I/II trial in high-risk or node positive, homologous recombination unselected, PCa. Patients received 6 months of ADT, AAP, niraparib and SBRT to the prostate (37.5-40 Gy) +/- pelvic lymph nodes (25 Gy). Focal prostate/nodal boosting was permitted. The phase I primary endpoint was the maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method (3 dose levels: 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT). Dose limiting toxicities (DLT) were any persistent grade 4+ hematologic toxicity or any grade 3+ rectal/urinary toxicity at least possibly related to treatment as assessed by CTCAE v5.0. Patient reported quality of life (QOL) was assessed with the EPIC-26 short form. Linear mixed models were used to compare scores over time. Results: Accrual began in Nov. 2020 with a transition from phase I to phase II in May 2023 after enrolling 54 men. Median follow-up of the phase I cohort is 12.1 months (IQR 9.4-18.9), 80% (n=43) had Grade Group 4-5, median PSA was 17 ng/mL (range, 1-73), 15% (n=8) had cN+ disease, and 76% (n=41) received nodal RT. There were 0 DLTs to date, no grade 3+ rectal or urinary toxicities, and 5 serious adverse events at least possibly attributable to study treatment (anemia, non-rectal gastrointestinal, syncope, infection, musculoskeletal). The most common grade 3 toxicities were hypertension (n = 11, 21%) and leukopenia (n=6, 11%). Transient dose reductions or holds of AAP or niraparib occurred in 10 and 11 patients, respectively. There were no statistically significant declines in patient reported urinary QOL at 6- or 12-months post-treatment compared to baseline (all p >0.15). A transient decline in bowel QOL at 6-months occurred (p<0.01), which improved by 12-months (p=0.16). Conclusions: Our phase I findings support the short-term safety and tolerability of the combination of SBRT to the prostate and nodes, ADT, AAP, and niraparib at an MTD of 200 mg in men with high-risk or node positive PCa. Our trial completed phase II enrollment in May 2024, and longer-term safety, efficacy, and genomic correlations will be presented in the future. Clinical trial information: NCT04194554 .

24 Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P < 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation.

9 Background: Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. We aim to identify factors predictive of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) from a consortium database from 10 academic institutions. Methods: 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA ( ≥ 0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (N/C ADT) were included. Cumulative incidence and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression and Cox proportional hazards methods for PCSM and ACM. Results: Median follow-up was 5 years from SRT completion and 8 years from date of RP; 24% had pathologic Gleason score (GS) of ≤ 6, 56% GS 7, and 19% GS ≥ 8; 56% extraprostatic extension (EPE), 18% seminal vesicle invasion (SVI), 58% positive surgical margins, and 16% received N/C ADT. Median age at RP and SRT were 62 years (IQR 56-66) and 64 years (59-69), respectively. Median SRT dose was 66 Gy (IQR 65-68) and median pre-SRT PSA was 0.5 ng/mL (IQR 0.3-1.1). MVA performed from SRT completion date demonstrated higher pre-SRT PSA (HR = 2.1), higher GS (GS 7 vs. ≤ 6: HR 2.0; GS ≥ 8 vs. 6: HR 3.3) , SVI (HR 2.5), year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR 2.9, HR 2.5, HR 3.6, respectively) were significantly associated with higher PCSM. These same variables were all significantly associated with higher PCSM and ACM rates calculated from both SRT completion date and date of RP. Conclusions: Initiation of early SRT at lower post-operative PSA levels following RP is associated with reduced risk of PCSM and ACM, even when calculated from RP date to account for lead time bias. Other factors significantly associated with PCSM include higher GS, SVI, and earlier year of SRT. [Table: see text]