Kwak, Lucia

5013 Background: There is no established role for the use of docetaxel with ADT and RT for HRLPC, with mixed results seen in prior RCTs. Prior work from ICECaP (Ravi et al, Eur Urol 2024) has shown that patients (pts) with very high-risk disease (i.e. 2 or 3 risk factors [RFs]: Gleason ≥8, PSA >20, ≥cT3 and/or cN1) have the poorest outcomes with RT+ADT for HRLPC, with 5-year metastasis-free survival (MFS) of ≤80%. We aimed to perform an IPD meta-analysis of the role of docetaxel with ADT+RT for HRLPC and specifically evaluate whether patients with very high-risk disease benefit from the addition of docetaxel. Methods: IPD from RCTs involving pts with HRLPC treated with RT+ADT +/- docetaxel collated by ICECaP were analyzed. “High-risk” disease was defined as presence of 1 RF and “very high-risk” disease as 2-3 RFs and/or cN1 disease. The primary outcomes of interest were MFS and overall survival (OS). Hazard ratios (HR) for MFS and OS were estimated using Cox regression, stratified by year of randomization and adjusted for age at randomization and ECOG performance status. 5-year MFS and OS rates were estimated using the Kaplan-Meier method. Subgroup analyses were performed according to the severity of disease (high- and very high-risk), and p-values for interaction were tested using the likelihood ratio test. Results: 1690 pts treated on 4 RCTs (GETUG-12, DFCI 05-043, STAMPEDE, RTOG-0521) between 2002-2015 were eligible. Median age was 65, median PSA was 23 (IQR 10-48); 154 (9%) pts had cN1 disease and 1444 (85%) received long-term ADT with RT. Median follow-up was 10 years (range: <1-15). Overall, the addition of docetaxel to RT+ADT was not associated with a significant benefit in MFS (HR=0.89 [0.76-1.05], p=0.160) or OS (HR=0.88 [0.74-1.05], p=0.167). Though there was some evidence for favoring docetaxel in pts with very high-risk disease (n=1054; MFS HR=0.86 [0.71-1.05]; OS HR=0.85 [0.68-1.07]) compared to high-risk disease (n=636; MFS HR=0.97 [0.74-1.27]; OS HR=0.95 [0.71-1.28]), there was no evidence of a significant difference in treatment effect by risk group (p-interaction >0.1). 5- and 10-yr MFS and OS in pts with high- and very high-risk disease, stratified by receipt of docetaxel, are shown in the Table. Conclusions: Some HRLPC pts with very high-risk disease may benefit from the addition of docetaxel to RT+ADT. Biomarker evaluation within this group may identify those who are candidates for treatment intensification with docetaxel with RT+ADT (+/- androgen receptor pathway inhibitors) in HRLPC. % (95% CI) High risk Very high-risk RT+ADT RT+ADT+docetaxel RT+ADT RT+ADT+docetaxel 5yr MFS 87 (82-90) 90 (86-93) 74 (71-78) 80 (76-83) 5yr OS 90 (86-93) 93 (90-96) 84 (80-86) 89 (86-92) 10yr MFS 67 (61-72) 71 (65-76) 51 (46-55) 55 (49-60) 10yr OS 74 (69-79) 77 (72-82) 62 (57-67) 67 (62-72)

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.