Lewis, Brian E.

e17064 Background: Analyses of clinical trials data suggest thatBlack men have equal or even improved overall survival (OS) with certain treatments for mCRPC compared with other races. Moreover, retrospective analysis of the PROCEED registry indicated that Black men who received Sip-T, an autologous cellular immunotherapy, had longer survival compared with other men with mCRPC. The Abi Race and PANTHER clinical trials prospectively assessed the effect of ARPIs on clinical outcomes among Black and White patient (pt) cohorts, and included pts who had received Sip-T either prior to or during study. We combined data from Abi Race and PANTHER to investigate associations between OS, Sip-T and race. Methods: Data from the Abi Race (N=100) and PANTHER (N=93) studies were retrospectively pooled for this analysis. Propensity scores for Sip-T treatment were calculated based on Karnofsky performance status, race, Gleason score, and study. Kaplan-Meier estimates for OS, with and without inverse propensity score weighting, were generated and stratified by Sip-T use. This analysis was stratified by race to examine whether the relationship between Sip-T use and OS differed by race. Results: Of the 93 Black pts and 100 White patients included from both studies, 123 patients did not receive Sip-T, while 70 patients did (60 before study, 10 on study). Pts who received Sip-T had a median OS (mOS) of 44 months (95% Confidence Interval (CI) 39, NR) compared to 36 months (95% CI 31, 48) for those who did not. Weighted by propensity scores, Black men who received Sip-T had a mOS of 72 months (95% CI 43, NR), while those who did not had a mOS of 38 months (95% CI 30, NR). Among White men, patients who received Sip-T had a mOS of 39 months (95% CI 30, NR), while those who did not had a mOS of 32 months (95% CI 29, 48) (see Table). Conclusions: Our findings from an investigator-led retrospective analysis independent of sponsors provide independent clinical trial support of prior retrospective findings that suggest Black men with mCRPC who receive Sip-T may have a greater OS than White men. While our analysis controlled for factors that may influence the use of Sip-T, it is limited by potential unmeasured confounders or timing of Sip-T. Further, adequately powered prospective trials specifically evaluating outcomes with Sip-T by race in earlier clinical settings are needed. Drug support and funding for Abi Race and PANTHER were provided by Janssen Scientific Affairs, LLC. Death counts and median overall survival (mOS) in months by race and Sipuleucel-T use. Black Men White Men Sipuleucel-T use Deaths / Total N No 36 / 64 38 / 59 Yes 12 / 29 24 / 41 Unweighted mOS (95% CI) No 36 (29, NR) 32 (29, 48) Yes 72 (43, NR) 39 (31, NR) Weighted mOS (95% CI) No 38 (30, NR) 32 (29, 48) Yes 72 (43, NR) 39 (30, NR) NR = not reached, mOS = median overall survival, CI = confidence interval.

5074 Background: PC commonly expresses PSMA and has dose-responsive radiosensitivity. 177Lu-based radioligands usually use an empiric dosing regimen. This 1st dose-escalation study of 177Lu-PSMA-617 employed a dose-dense fractionation schedule intended to allow delivery of higher total doses to overcome radioresistance due to repopulation. Here, we report mature results of the study. Methods: Progressive mCRPC following > 1 potent ARPI (e.g., abi/enza) and chemo (or unfit/refuse taxane) without limit of # prior therapies provided adequate organ function and ECOG PS 0-2. Treatment: single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In Ph I dose-escalation, patients (pts) received one cycle of 7.4 - 22 GBq followed by Simon 2-stage Ph II at 22.2 GBq. PSMA expression was not required for treatment, but pre- and post-treatment 68Ga-PSMA11 PET/CT and/or 177Lu-PSMA-617 SPECT done. Primary efficacy by PSA changes with 2ndary outcomes with CT/bone scans, PSMA PET, circulating tumor cell (CTC; CellSearch) counts, plasma DNA (PCF_SELECT), and survival. Results: Between 1/2017 – 2/2021, 50 pts treated with median PSA 164.3, 35 (70%) CALGB (Halabi) poor risk. 47 (94%) bone, 38 (76%) nodal, 12 (24%) lung, 5 (10%) liver mets (4 additional pts with PSMA PET+ liver mets not apparent on CT). 29 (58%) with prior >2 ARPI, 29 (58%) with >1 chemo, 14 (28%) with Ra-223, 2 (4%) with 177Lu-J591. 27 (54%) treated at 22 GBq. No dose-limiting toxicity during Ph I. 38 (76%) with any PSA decline, 27 (54%) with >50% PSA. Median rPFS 8.3 mo [5.6-16.7], and OS 15.7 mo [10.9-20.6]. Of 17 RECIST measurable, 6 (35.3%) responded, 7 (41.2%) stable, 4 (23.5%) progressed. Of 31 with paired CTC counts, 16 (52%) decreased, 5 (16%) were stable; 10 (32.3%) converted to favorable/undetectable. Plasma DNA with high allele-specific ploidy and ARcopy number gain associated with OS (univariate). Treatment emergent adverse events (TEAE): 32 (64%) dry mouth, 22 (44%) pain flare, 22 (44%) fatigue, 19 (38%) nausea, 15 (30%) anemia, 15 (28%) thrombocytopenia (plts), 9 (18%) neutropenia (ANC). All TEAEs restricted to grade (Gr) 1-2 except 6 (12%) with Gr 3 anemia, 2 (4%) Gr 3/4 plts, 1 (2%) Gr 3 ANC. TEAE incidence and Gr were not related to dose. On multivariable analysis, 177Lu dose administered (p=0.09), CALGB risk (p=0.04), prior chemo (p=0.009), associated with OS; dose (p=0.1), CALGB risk (p=0.2), and AR copy number (p=0.2) associated with PSA50 decline. Baseline PSMA imaging (by imaging score or SUVmax) was not associated with OS or response. Conclusions: A single-cycle of fractionated-dose 177Lu-PSMA-617 is safe. Despite no pre-selection for PSMA expression, most had PSA decline with favorable PFS and OS compared to historical controls and similar to PSMA-selected targeted radionuclide studies administering multiple cycles in a less dose-intense approach. Clinical trial information: NCT03042468 .

5003 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [68Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177Lu-PSMA-617 and 6.5 months for ARPI change. 177Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]

Abstract Background: Advanced prostate cancer is defined as metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC). Newer and aggressive treatments are leading to increasing lifespans in this population. As such, studying quality of life could have a large impact on the survivorship experience. An important component of quality of life is financial toxicity, defined as the financial burden and distress that can arise for patients and their families because of cancer treatment. Objectives: To understand the prevalence and predictors of financial toxicity in advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a prospective cohort of patients with newly diagnosed mHSPC or CRPC enrolling in 15 countries. Financial toxicity was collected using the EORTC QLQ-C30 (“has your physical condition or medical treatment caused you financial difficulties?”) at enrollment and every three months thereafter. For this analysis, we studied 997 patients cared for at 37 US sites enrolled from 7/2017 to 7/2023. We examined baseline and longitudinal reports of financial toxicity across clinical and demographic factors: age at enrollment, race and ethnicity, disease state, marital status, education, employment, military status, and type of health center. We conducted adjusted risk difference analysis and multivariable regression modeling to identify predictors of financial toxicity using a generalized estimating equations approach to calculate odds ratios (OR and 95% confidence intervals, CI). Results: At enrollment, 125 (13%) patients reported experiencing “quite a bit” or “very much” financial toxicity. 21% of Black patients experienced toxicity compared to 10% of White patients. Even after incorporating all other predictors, Black patients experienced 5% (95% CI: 0, 11) greater toxicity than White patients. Independently of other predictors, patients >75 experienced 11% (CI: -17, -4) lower toxicity compared to those <65 years (while patients in the 65-74 group experienced 6% less, CI: -12, 1). Toxicity was 6% greater in patients with mHSPC (CI: 2, 10) than in patients with CRPC, and disabled or unemployed patients were at substantially higher risk. In the multivariable longitudinal analyses, older age (> 75) remained associated with significantly lower odds for financial toxicity (OR: 0.30, 0.15-0.61) while mHSPC (OR: 1.91, 1.14-3.20) and being unemployed (OR: 2.69, 1.03-6.99) or disabled (OR: 5.14, 2.29-11.6) were associated with higher odds. Conclusions: Financial toxicity is prevalent in advanced prostate cancer, especially in patients who are Black, younger than 75, diagnosed with mHSPC, or unemployed/disabled. These results may inform identification of patients at high risk for financial toxicity to support delivery of patient-situation-informed care by clinicians and targeted aid for patients at highest risk. Citation Format: Isani Singh, Bailey Vaselkiv, Emily Rencsok, Karen Autio, Deborah Enting, Alicia Morgans, Joel Nowak, Kevin Kensler, David Nanus, Robert Dreicer, Brian Lewis, Oliver Sartor, Elisabeth Heath, Phillip Kantoff, Deborah Kaye, Daniel George, Lorelei Mucci. Financial toxicity among patients with advanced prostate cancer in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3410.

AbstractBackgroundThe goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.MethodsAfrican American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.ResultsA total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely‐pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non‐BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African‐Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.ConclusionsIn metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non‐BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.