5015 Background: Antibodies and small molecule ligands target PSMA with different kinetics and biodistribution, with certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel less accessible to large antibodies. Alpha emitters such as 225Ac have high potency, but short range. We report dose-escalation plus expansion cohort results of a first in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and chemo (or unfit/refuse chemo) without limit of # prior therapies (including Ra-223 or prior 177Lu-PSMA) provided adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Dose-escalation was in single-subjects x4 followed by 3+3 with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade (Gr) 4 heme toxicity or Gr 3/4 non-heme tox. Imaging, genomic, patient-reported outcomes (PRO), and immune correlates embedded. Results: 32 men were treated with a single dose of 225Ac-J591 on 7 dose levels with expansion at the highest dose level (n = 16). Median age 69.5 (range 52-89), PSA 149.1 (4.8-7168.4); 75% with >2 prior ARPI, 62.5% chemo, 28% Ra-223, 43.7% 177Lu-PSMA. One (3.1%) CALGB (Halabi) good prognostic risk, 8 (25%) intermediate, and 23 (71.9%) poor risk. While PSMA uptake was not a prerequisite for treatment, of 28 with pre-treatment PSMA PET, none had tumor SUVmax < liver, 5 (17.8%) with tumor SUVmax 1-2.5x liver, 2 (7.2%) with tumor SUVmax 2.5-5x liver, and 21 (75%) with tumor SUVmax > 5x liver SUVmean. 1 of 6 in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets) with 0 of 6 at the highest dose level (93.3 KBq/Kg) and this dose was expanded. High Gr AEs were restricted to hematologic: In addition to DLT, 4 (12.5%) Gr 3 platelets and 2 (6.2%) with Gr 3 neutropenia. Non-heme AE’s were restricted to Gr 1/2 and included: 10 (31.2%) fatigue, 5 (15.6%) pain flare, 14 (43.7%) nausea, 8 (25%) with Gr 1 xerostomia (of which 5 received prior 177Lu-PSMA), 12 (37.5%) AST elevation. Despite prior treatment including 177Lu-PSMA and no selection for PSMA expression, 22 (68.7%) with any PSA decline, 12 (37.5%) with > 50% PSA decline. Of 21 with paired baseline and 12-wk CTC counts, 12 declined (5 converting from unfavorable to favorable and 5 converting detectable to 0), 5 remained 0, 4 increased. In the subset with PRO data, pain scores by BPI-SF tended to improve by wk 12. Following a single dose of 225Ac-J591, median PFS 7.2 months [95% CI 4.6-NR], median OS 10.9 months [7.6-21.1]. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity. Based upon these results, a follow up study [NCT04506567] testing multiple and fractionated dosing of 225Ac-J591 is underway. Clinical trial information: NCT03276572.

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BackgroundNeutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate‐specific antigen (PSA) response and survival in men treated with prostate‐specific membrane antigen (PSMA)‐targeted radionuclide therapy (TRT).MethodsData of 180 men with metastatic castration‐resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu‐J591, 90Y‐J591, 177Lu‐PSMA‐617, or 225Ac‐J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS).ResultsA total of 94 subjects (52.2%) received 177Lu‐J591, 51 (28.3%) 177Lu‐PSMA‐617, 28 (15.6%) 225Ac‐J591, and 7 (3.9%) 90Y‐J591. The median NLR of 3.75 was used as cut‐off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99–1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02–1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003–1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05–1.94, p = 0.024).ConclusionsNLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA‐TRT.

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.

5055 Background: PSMA-TRT is a promising investigational treatment for patients with mCRPC. Expected short-term toxicities associated with PSMA-TRT include dose-dependent myelosuppression and xerostomia. However, there is a lack of information regarding long-term effects of PSMA-TRT on marrow, renal, and liver function. Additionally, potential organ dose limits for radiation are derived from studies of external beam radiation, which may not be applicable to TRT. Methods: Men treated on prospective clinical trials of PSMA-TRT, from 2003 through 2020 with at least six months of follow-up were included. Variables included treatment, co-morbidities, baseline and most recent renal, liver, and marrow function, along with respective short-term ( < 6 months) and long-term toxicities. AEs were graded using CTCAE version 5 and attribution was assessed with most recent clinical follow up. Multivariable logistic regression was used to control for type of TRT, comorbidities, and subsequent therapies. Results: 71 (59.7%) patients who received 177Lu-J591, 30 (25.2%) 177Lu-PSMA-617, 11 (9.2%) 225Ac-J591, and 7 (5.9%) 90Y-J591 were included, with median follow up 18 months (range 6-133). Long-term (most recent) laboratory values and AEs are summarized in the table. A majority of AEs were attributed to alternate etiologies. 5 of 14 cases of grade (Gr) ≥2 creatinine increase, 3 of 36 cases of Gr ≥2 platelets, 2 of 14 cases of Gr ≥2 bilirubin, 1 of 15 cases of Gr ≥2 AST increase, and 1 of 5 cases of Gr ≥2 ALT increase were deemed possibly related to PSMA-TRT. Only two Gr ≥3 AEs were attributed to possibly being related to PSMA-TRT: one case of Gr 4 creatinine elevation and one case of Gr 3 ALT elevation. On multivariable analysis, alpha-TRT was associated with hepatic AEs (OR 4.38, p = 0.047), and there was a trend towards higher Charlson Comorbidity scores associating with hematologic AEs (OR 1.27, p = 0.095). Conclusions: This is the largest analysis to-date of long-term AEs in patients who have received PSMA-TRT. Long-term effects on renal, liver, and marrow function are infrequent.[Table: see text]

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