Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in salivary glands, small bowel, and kidney; SMLs rapidly diffuse to all PSMA+ sites and are excreted by the kidneys within hours. Alpha emitters have high potency over a short range whereas beta emitters have lower energy over a significantly longer range. We hypothesized that combining mAb and SML targeting plus combining alpha and beta emitters offered complementary benefits and would be safe and effective. Methods: A series of cell line and xenograft studies were performed to test mAb vs SML vs combo binding, uptake, and efficacy. A phase I/II clinical trial was initiated, enrolling patients with progressive, PSMA+ (by PSMA PET) mCRPC following potent AR pathway inhibition and chemotherapy (or chemo ineligible/refused)[NCT04886986]. The primary endpoint of phase I is assessment of dose-limiting toxicity (DLT) with secondary endpoints of response, progression-free and overall survival, genomic and imaging correlatives, and patient-reported outcomes. Results: Binding studies demonstrated that mAb plus SML binding was additive rather than competitive in LNCaP and CWR22Rv1 cell lines. Uptake of 177Lu-mAb plus -SML in LNCaP, CWR22rv1, and PC3/PSMA xenograft models demonstrated synergism, with 44-65% greater tumor radioactivity in combination than the sum of the individual agents. Intracellular tracking studies indicate that the mAb re-directs SML to lysosomes from recycling endosomes, maintains retention of SML in tumor cells, and, therefore, prolongs intra-tumoral radioactivity exposure. Survival was prolonged in animals receiving 225Ac-mAb plus 177Lu-SML vs either drug alone (or control). Nine men with median age 68 (range 55-87), PSA 140 (2.4-9614) have been enrolled in both of 2 planned dose-escalation cohorts. 89% with bone, 44% lymph node, 22% liver, 22% lung metastases; 88% with detectable CTC count (75% unfavorable). All had at least 1 metastatic lesion with PSMA PET SUVmax > liver SUVmean, with SUVmax of the single hottest lesion ranging from 11.6-69.9. For the primary endpoint, 0 of 3 with DLT in cohort 1, and with follow up ongoing, no DLT has occurred to date in 6 patients in cohort 2. Of evaluable patients, 5 of 6 with PSA decline (8-97% decline). Conclusions: Targeting PSMA with the combination of mAb and SML leads to synergistic radioactivity in preclinical studies. The combination on mAb and SML radiolabeled with alpha and beta emitters appears safe with short-term follow up with phase 2 enrollment planned. Citation Format: Scott T. Tagawa, Edward Fung, Muhammad O. Niaz, Mahelia Bissassar, Sharon Singh, Amie Patel, Angela Tan, Juana Martinez Zuloaga, Sandra Huicochea Castellanos, Jones T. Nauseef, Ana Molina, Cora Sternberg, David M. Nanus, Joseph Osborne, Neil H. Bander. Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT143.

TPS5100 Background: PSMA is overexpressed by most prostate cancers and can be successfully targeted by both antibodies (mAb) and small molecule ligands (SML), each with overlapping and distinct binding sites, kinetics, and biodistributions [Kratochwil Sem Nuc Med 2019]. mAbs are larger, with longer circulating times resulting in greater exposure to bone marrow, but lesser access to PSMA expression on luminal tissue ( e.g. salivary glands, small bowel, and kidney). In contrast, SMLs are rapidly excreted via kidneys and readily diffuse to all PSMA-expressing sites. Toxicities of 177Lu vary with these differences in biodistribution ( e.g. more hematologic toxicity with mAb, more xerostomia and nausea with SML, p < 0.001)[Niaz AUA 2020]. Alpha emitting isotopes have shorter ranges but high potency compared to beta emitters which have longer ranges, but lower linear energy transfer. In preclinical models, the combination of mAb plus SML has demonstrated additive binding in LNCaP, CWR22Rv1, and PC3/PSMA PC cell lines, and synergistic uptake of 177Lu-mAb plus 177Lu-SML in xenograft models. We developed a phase I/II study to test our hypothesis that concomitant mAb and SML targeting, plus the combination of alpha (225Ac) and beta emitters (177Lu), may offer complementary benefits in a safe and effective manner. Methods: Key eligibility criteria include progressive mCRPC (PCWG3), at least 1 prior AR pathway inhibitor and taxane chemotherapy (or ineligible/refused), and adequate organ function and performance status. PSMA PET/CT must have at least 1 lesion with SUVmax > liver SUV. Prior PSMA-based therapy with radioisotopes is not allowed. 177Lu-PSMA-I&T (PNT2002) will be administered as in the phase III SPLASH study (6.8 GBq q8w for up to 2 doses). The phase I includes up to two dose-escalation cohorts of concurrent 225Ac-J591 (30 & 40 KBq/Kg q8w x2) in a modified 3+3 schema. All subjects undergo 177Lu SPECT on Day 8 after each dose. The primary objective of the Phase I study is to determine the dose-limiting toxicity and recommended phase II dose (RP2D) for this combination. Primary objective of the Phase II study is to assess the proportion of patients with > 50% PSA decline after treatment. Secondary objectives include radiographic response rate (PCWG3-modified RECIST 1.1), biochemical and radiographic progression-free survival, overall survival, safety (CTCAE 5.0), CTC count changes and conversions, and patient-reported outcomes (FACT-P, BPI-SF, EQ-5D). Exploratory objectives include pre- and post-treatment PSMA-based imaging changes, effects of PSMA radionuclides on the microbiome, relationship between genomic alterations and response, and relationship between PSMA PET/CT results and outcome. The phase I was activated at Weill Cornell Medicine in May 2021. Following determination of the RP2D, a multicenter phase II is planned at Prostate Cancer Clinical Trials Consortium (PCCTC) in 2022. Clinical trial information: 04886986.

77 Background: Prostate Specific Membrane Antigen (PSMA) is a conserved cell surface protein in PC and is used for targeted imaging and therapeutics. Antibodies circulate longer than small molecules and are less likely to reach luminal PSMA on normal organs. Here we report PROs and longer-term AEs from the dose-escalation and expansion cohorts of a first-in-human study of combined monoclonal antibody and potent alpha emitter (225Ac-J591). Methods: Eligible subjects with mCPRC were administered 225Ac-J591. Initial to maximum doses were 13.3 to 93.3 KBq/kg). AEs are reporting using CTCAE v5 and PROs, including pain (BPI-SF) and quality of life (QOL, FACT-P), and associations with PSA response were also examined. Results: A total of 32 subjects (one enrolled in both dose-escalation and expansion) were treated with a single dose of 225Ac-J591 across 7 dose levels with expansion at the level (93.3 KBq/kg, n = 16). Median age 69.5 (52-89) and PSA 149.1 (4.8-7168.4). All subjects had at least 1 AE of any grade. Most common were fatigue (31/32, 1 Gr > 2), anorexia (25/32, all Gr 1-2), and thrombocytopenia (25/32, 3 Gr 3, 2 Gr 4). Xerostomia was observed in 14/32 subjects (all Gr 1), 7 of whom had prior 177Lu-PSMA. Pain flare was reported in 43% (17/32) subjects (11 Gr 1, 6 Gr 2). 19 had evaluable PROs at baseline and efficacy visit (week 12). Pain severity (p = 0.8) and interference from pain (p = 0.4) were unchanged from baseline to 12 weeks, yet better PSA response (by percent) was associated with reduced pain severity (r = 0.7, p = 0.0023). Despite at least one AE in each subject, total FACT-P was not significantly changed after treatment (p = 0.2), but emotional well-being declined over time (15 [10.0, 18.0] v 10.0 [7.5, 13.0], p = 0.011). Reduction in median emotional well-being reached clinically important score differences. When stratified by AE, subjects with xerostomia had lower FACT-P total scores, but no difference was observed between those with and without pain. PSA response was not associated with change in QOL or subscales. Conclusions: Pain and quality of life in subjects with mCRPC did not change, on average, from baseline to 12 weeks after treatment with 225Ac-J591. This is despite preliminary evidence of clinical efficacy being accompanied by frequent, treatment emergent AEs. A promising trend toward improved pain in those with PSA response warrants further analysis. Small numbers limited statistical power for testing other subgroup associations. Additional correlations with pretreatment sites of disease, performance status, and adverse event distribution are ongoing. Assessment of changes in PROs in the follow up studies [NCT04506567] are underway. Clinical trial information: NCT03276572.

37 Background: We have previously reported a dose-intense single-cycle of 177Lu-PSMA-617 was effective in pretreated patients with mCRPC without requiring PSMA-positive imaging for enrollment. Prior post-hoc analyses of these data using approximate quantification of exclusively the most PSMA-positive disease sites have demonstrated associations between PSA response and PFS with pre-treatment 68Ga-PSMA11-PET signal. Greater sophistication in pre- and post-treatment evaluation of PSMA-expression in tumor and normal organs may allow for better patient selection and prediction of toxicities. Methods: A total of 50 patients were treated on a phase I/II study of fractionated-dose (D1, 15) 177Lu-617-PSMA. Quantification using artificial intelligence (AI) were used to measure pre- and post-treatment PSMA signal intensity. Scoring cutoffs with confidence intervals around scan variation were empirically established from a subset of test/re-test of subjects within 24h without intervening therapy. A variety of measurements were performed including SUVmean across all detectable tumor lesions, volume of lesions, and SUVtotal (Total + Volume), as well as select normal organs and changes after treatment. Associations with survival were tested via Cox proportional hazard models in univariate analyses and associations with adverse events (AEs) and PSA responses were via assessed via Wilcoxon rank sum tests. Results: 13 subjects were selected to complete AI-based quantification and associated survival analyses. Among these, 10 (77%) experienced any PSA decline, with 8 (62%) with PSA50 and 3 (23%)with PSA90. Median overall survival (OS) was 17.0 mos (10, NA) via Kaplan-Meier estimates. In univariate analysis, pretreatment SUVmean was associated with improved PFS (HR 0.66, 95% CI 0.49-0.90, p = 0.009) and OS (HR 0.81, 95% CI 0.65-1.00, p = 0.048). The metrics most strongly associated with PSA50 were pretreatment SUVmean (median [IQR]: 7.66 [6.52, 10.54] v 3.50 [3.02, 3.56], p = 0.019) and SUV Total (14982 [11110, 20595] v 1303 [576, 1512], p = 0.019), and change in Volume (-27 [-44, -20] v 145 [38, 154], p = 0.006) and SUVtotal (-57 [-67, -35] v 132 [9, 269], p = 0.030). Subjects with xerostomia had higher salivary gland SUVmax (pretreatment and change in after treatment). Those with pain flare had lower pretreatment SUV scores (Mean, Max, Total) in unaffected portions of bony skeleton. Conclusions: Sophisticated AI-based quantification analysis of PSMA expression on pre- and post-treatment 68Ga-PSMA11-PETs demonstrate associations with treatment efficacy (PSA response, OS), and associations between patient experience (AEs) and PSMA expression in non-tumor tissues. Expansion of this algorithm to a larger patient cohort may improve our ability to anticipate toxicity by body-wide PSMA detection and predict treatment response. Clinical trial information: NCT03042468.

e17007 Background: Prostate-specific membrane antigen (PSMA) is overexpressed on most prostate cancers (PCs), a fact that has been exploited to perform both targeted imaging and treatment. PSMA-based PET imaging allows for more sensitive detection of PC and can be useful even in the context of negative CT and bone scans. Prior to 2021, research protocols using PSMA-PET (PET) were common at large academic centers, but will likely be more commonplace as standard of care (SOC) after recent FDA approval. With a change in SOC imaging, the impact of cost to patients must be examined. We hypothesize that socioeconomic and demographic-based care disparities may widen and access may narrow in the face of these changes. Methods: We collected demographic data on patients with PC from Weill Cornell Medicine (WCM), Brooklyn Methodist Hospital (BMH), and Columbia University Medical Center (CUMC) who received a PSMA PET scan between 1 January 2018 and 31 January 2022. Data collected included age, zip code, primary language, self-reported race and ethnicity, and type of insurance coverage. Zip codes were used to estimate income strata of patients using publicly-available 2018 IRS adjusted gross income (AGIs) as follows ($): < 25k, 25k-50k, 50k-75k, 75k-100k, 100k-200k, and > 200k. Any AGI strata comprising > 20% of population was counted. Patients were divided into four cohorts: those who had a scan (1) as part of therapeutic-based studies for mCRPC, (2) non-therapeutic imaging studies, (3) as a part of a cost-recovery study with an out-of-pocket cost of $1054, and (4) commercial use under post-approval standards of care (SOC) billed to insurance. Proportion of self-reported race in each cohort was compared against overall race distribution for prostate cancer registry from WCM and CUIMC (Table). Results: 896 patients underwent PSMA PET. Approximately half of all scans were in Cohort 4 (49%, n = 368) including all BMH scans. CUMC scans were 90% in Cohort 2 (122/136). In Cohort 1, 2, and 3, > 90% of subjects resided in zip codes with AGI > $100k. In Cohort 4, 84% resided in zip codes with AGI > $100k. Overall 70.4% of subjects identified as White, 8.3% Black or African American, 3.5% Asian, 4.4% Other, and 13.5% were unknown/or declined. African American/Black was most represented on Cohort 4 (11%), and least represented in Cohort 1 (5%). Conclusions: White patients comprise the largest proportion or PET scans whereas non-white groups are underrepresented across all cohorts. Access to PETs has appeared to improve for lower AGI, non-white patients following FDA approval and insurance coverage. It will be critical to assure equitable access across all demographic groups as deployment of PET scanning becomes the new standard of care.[Table: see text]