Purpose: Prostate-specific membrane antigen (PSMA)-directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule.Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc-EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc-EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging.Results: 99mTc-EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc-EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer-like morphology.Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

4534 Background: HC-7366 is a novel, selective, potent activator of general control nonderepressible 2 (GCN2) kinase, regulating metabolic stress via the integrated stress response. Our preclinical studies in RCC demonstrated that prolonged GCN2 activation by HC-7366 resulted in antitumor activity accompanied by inhibition of HIFs and cell cycle progression. Furthermore, combination with belzutifan (BEL) results in superior preclinical efficacy, accompanied by inhibition of HIF signaling and cell-cycle progression, supporting clinical evaluation of the combination in RCC. Methods: Patients with advanced ccRCC previously treated with ≥1 anti-PD/PD-L1 and ≥1 VEGF-TKI were enrolled into HC-7366 monotherapy (60 mg QD) or a dose-escalation/expansion cohort of HC-7366 (20, 40, 60 mg QD) with BEL (120 mg QD). Primary objectives were safety, tolerability, and investigator-assessed ORR per RECIST v1.1. Enrollment in escalation and expansion is complete; second expansion is ongoing. Results: As of the data cutoff 10 Dec 2025, 69 patients received study treatment: 16 monotherapy and 53 combination (7 at 20 mg, 22 at 40 mg, 24 at 60 mg). Median prior therapies were 3 (range 1-5) in monotherapy and 2 (range 1-4) in combination. Most TEAEs were Grade (Gr) 1-2. Gr 3 events were mainly hematological (anemia) and gastrointestinal (nausea and diarrhea), with one DLT (Gr 3 nausea, 40 mg combination). In efficacy-evaluable patients, the 40 mg combination demonstrated the best overall response rate (BORR) of 36.8%, including a confirmed ORR (cORR) of 26.3%, disease control rate (DCR) of 89.5%, and primary progressive disease (PD) rate of 10.5%. The 60 mg combination had a BORR of 31.6%, with a cORR of 31.6%, DCR of 84.2%, and primary PD rate of 15.8%. In monotherapy, BORR of 15.4% and DCR of 61.5% were observed. Early efficacy signals at 40–60 mg align with the preclinical projected maximal efficacious dose range. Conclusions: HC-7366, alone or in combination with BEL, was generally well tolerated. Preliminary efficacy analyses indicate favorable disease control, characterized by a high DCR and low primary PD. Clinical trial information: NCT06234605 . Efficacy and safety data by cohort. Monotherapy60 mgN=13 HC-7366 + BELZ20/120 mgN=7 HC-7366 + BELZ 40/120 mg N=19 HC-7366 + BELZ 60/120 mg N=19 Median follow-up (mo) 16.9 13.4 11.2 8.5 BORR /cORR (%) 2 (15.4) /0* 0 /0 7 (36.8) /5 (26.3)​ 6 (31.6) /6 (31.6) DCR (%) 8 (61.5)​ 5 (71.4)​ 17 (89.5)​ 16 (84.2)​ Primary PD (%) 5 (38.5) 2 (28.6) 2 (10.5) 3 (15.8)​ PFS 6 mo (%) 15.4 42.9 57.9 73.7 Any Gr /Gr 3 AEs 15 (93.8) /9 (56.3) 7 (100) /4 (57.1) 22 (100) /16 (72.7) 24 (100) /17 (70.8) Gr 3 Anemia /Hypoxia 0 /2 (12.5) 2 (28.6) /1 (14.3) 5 (22.7) /2 (9.1) 5 (20.8) /2 (8.3) Gr 3 Nausea /Diarrhea 2 (12.5) /3 (18.8) 0 /1 (14.3) 1 (4.5) /0 2 (8.3) /0 Dose Red /Discont. 6 (37.5) /2 (12.5) 1 (14.3) /0 11 (50.0) /2 (9.1) 7 (29.2) /3 (12.5) *PRs not confirmed due to emergence of brain metastases.

Immunotherapy has shown limited efficacy in metastatic castration-resistant prostate cancer (mCRPC), highlighting the need for noninvasive tools to monitor treatment-related biological changes. This case series evaluated exploratory metabolic imaging correlates using [18F]-FDG PET/CT in mCRPC patients enrolled in a Cancer Immunotherapy Trials Network (CITN) trial of sipuleucel-T (sip-T) with or without recombinant interleukin-7 (IL-7). Among 54 enrolled patients (NCT01881867), three underwent serial [18F]-FDG PET/CT imaging at baseline and following sip-T therapy. Imaging assessed tumor metabolic activity and potential immune-related metabolic changes, based on the premise that immune processes may influence FDG uptake. Patient 1, treated with sip-T alone, demonstrated progressive sternal metastasis with stable SUVmax and marked increases in metabolic tumor volume (MTV: 10.1-34.5) and total lesion glycolysis (TLG: 43.4-145.8), consistent with poor prognosis. Patient 2 showed minimal tumor avidity but transient increases in splenic SUVmax and SUVmean following sip-T, which may reflect treatment-related or immune-associated metabolic activity. Patient 3, treated with sip-T plus IL-7, demonstrated a 33% reduction in SUVmax, stable disease on follow-up imaging, decreased PSA levels, and metabolic changes consistent with treatment response in this individual case. These findings were observed in a single patient and are considered exploratory and hypothesis-generating only. [18F]-FDG PET/CT imaging may provide exploratory insights into metabolic changes in tumors and immune-related organs in mCRPC. Metabolic changes in tumors and immune organs may provide insights into treatment-associated biological effects. Larger studies are warranted to validate these findings.

Prostate Cancer Working Group 4 recommends using prostate-specific membrane antigen (PSMA) PET for response assessment of patients with androgen pathway receptor modulator-resistant prostate cancer treated with 177Lu-PSMA-617. For that purpose, the time interval between baseline PSMA PET and initiation of therapy is critical as interim disease progression may influence the performance of PET as a response assessment tool. Methods: We visually assessed the frequency of interim disease progression seen on the first posttherapy 177Lu-PSMA-617 SPECT/CT in 87 patients with androgen pathway receptor modulator-resistant prostate cancer. The time interval between baseline PSMA PET and initiation of therapy, pretherapy prostate-specific antigen (PSA) measures, and treatment outcomes between patients with or without interim progression on SPECT/CT were also compared. Results: For the 32 patients (36.8%) with interim progression, the PET to therapy interval (88 d) was significantly greater than those without progression (42 d, P < 0.001) despite adjusting for age, Gleason grade, and PSA doubling time. A time interval between baseline PSMA PET and initiation of therapy exceeding 30 d was seen in approximately 94% of patients with interim progression. PSA response and overall survival were not impacted by interim progression. Conclusion: Baseline PSMA PET may not represent the true disease status if the first cycle of 177Lu-PSMA-617 occurs more than 30 d after baseline PET.

The NCCN Guidelines for Testicular Cancer provide recommendations for the multidisciplinary approach to the diagnostic workup, treatment, and follow-up for testicular germ cell tumors, including both seminoma and nonseminoma. These NCCN Guidelines Insights discuss the current treatment recommendations and supporting clinical data for seminomas as presented in Version 2.2025 of the NCCN Guidelines for Testicular Cancer.

TPS4614 Background: HC-7366 is a novel, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Prolonged or hyper-activation of GCN2 suppresses general protein synthesis and induces cell cycle arrest, ultimately leading to apoptosis. HC-7366 decreases HIF expression in tumor and immunosuppressive myeloid cells and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function in tumor cells. In CDX RCC xenografts, HC-7366 combined with belzutifan (BLZ) exhibited tumor regression, and in BLZ-resistant PDX models, HC-7366 demonstrated monotherapy (mono) antitumor activity. These preclinical effects of HC-7366 suggest potential therapeutic benefit in clear cell renal cell carcinoma (ccRCC) and rationale for combinations with HIF2α antagonists. Mechanism of action studies identified biomarkers of pathway engagement which may be predictive of efficacy (Stokes, AACR 2024, Abstract 4615). HC-7366 75 mg was determined to be the maximum tolerated dose (MTD) in a previous phase 1a study in patients (pts) with solid tumors which did not include ccRCC ( data on file with sponsor ). Methods: This is a multicenter, open-label, phase 1b dose escalation and expansion study evaluating safety, tolerability, MTD, recommended phase 2 dose (RP2D) of HC-7366 + BLZ (combo) in pts with advanced / metastatic RCC, predominantly clear cell histology. Additionally, HC-7366 60 mg mono (up to 20 patients) is assessed in parallel. In dose escalation, HC-7366 (20, 40, 60 mg po qd) + BLZ (120 mg po qd) is evaluated using a modified Toxicity Probability Interval design in up to 20 pts. Dose expansion will evaluate two HC-7366 doses selected from escalation + BLZ (15 pts/dose level). Tumor response will be assessed by CT scans every 8 wks (RECIST v1.1). Secondary endpoints include ORR, DOR, TTR, DCR, PFS, and OS. PK data will be profiled, and exploratory objectives include pharmacodynamic marker evaluation in tumor biopsies and peripheral blood samples. Key eligibility criteria include 1-3 prior therapies for the combo cohorts (naïve to BLZ/ HIF-2α inhibitors) and 1-4 prior therapies for the mono cohort (may include BLZ/ HIF-2α inhibitors), >1 measurable lesion, and willingness to provide biopsy or archival tumor samples at two timepoints. Escalation Dose levels 1 and 2 of the combination cohorts have been cleared and enrollment is ongoing for Dose level 3 (60 mg + BLZ), Expansion Dose Level 1 (40 mg + BLZ) and the mono cohort (60 mg HC-7366) at 20 US sites. The trial is sponsored by HiberCell, Inc. in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson pmattson@hibercell.com , 651.312.5831. Clinical trial information: NCT06234605 .

PURPOSE:Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC. PATIENTS AND METHODS:This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported. RESULTS:As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. CONCLUSIONS:Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.

Representativeness of study participants

167 Background: Addition of docetaxel (D) to ADT has demonstrated improved overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC). In this post hoc OS analysis of the CHAARTED trial (NCT00309985), we report 10-year OS and cause of death (COD) by baseline clinical factors, PSA nadir at 6 months in mHSPC patients treated with ADT +/- D. Methods: An updated survival sweep was conducted in July 2024. Patients were prospectively identified by the state of metastatic disease (metachronous/prior local therapy vs. synchronous/no prior local therapy) and low volume (LV) vs. high volume (HV; visceral and/or ≥4 bone metastases with one lesion beyond the vertebral bodies or pelvis) disease. OS defined as time from 6 mos post randomization to death was calculated using the Kaplan-Meier method and compared between PSA nadir (<0.2 vs. ≥0.2) groups using the log rank test. Results: A total of 334 patients achieved PSA nadir of <0.2 at any timepoint with a median time to PSA nadir of 4.8 months. At 6 months, PSA nadir <0.2 was seen in 204 (26.8%) patients. Patients with PSA nadir <0.2 had significantly better median OS in both ADT + D (100.3 vs. 45.4 mos; P<0.0001; Table) and ADT (116.8 vs. 31.8 mos; P<0.0001) arms. This prognostic impact was significant across prespecified prognostic subgroups. Of the 101 patients who achieved a PSA of < 0.2 at 6 mos, the COD was ‘prostate cancer’ in 58.4% (n=59), ‘other’ in 14.9% with 26.7% being unknown. Of the unknown/missing (n=27), 10 patients died without a record of having progression. In the PSA nadir ≥0.2 group, the reported COD was ‘prostate cancer’ in 78.2% with 6.5% being ‘other' and 15.4% being unknown/missing. Conclusions: Compared with patients with PSA ≥0.2, PSA nadir of <0.2 at 6 months was associated with less prostate cancer deaths and more than doubling of the median OS with approximately 50% of patients alive at 8 years across treatment and all prespecified prognostic groups except de novo high volume treated with ADT alone. Clinical trial information: NCT00309985 . Outcomes by PSA nadir at 6 months in overall population and pre-specified subgroups. ADT+ D ADT # Death/N Median OS (95% CI; months) p-value # Death/N Median OS (95% CI; months) p-value Overall 6-month PSA <0.2 66/127 100.3 (70.4, NA) <0.0001 35/77 116.8 (87.3, 141.5) <0.0001 6-month PSA ≥0.2 203/256 45.4 (39.2, 51.6) 246/301 31.8 (26.3, 38.1) Denovo HV6-month PSA <0.2 20/39 93.5 (45.9, NA) 0.0001 7/11 74.7 (37.4, NA) 0.007 6-month PSA ≥0.2 135/166 39.5 (32.8, 48.5) 162/183 26.4 (23.5, 32.0) Metach HV6-month PSA <0.2 12/23 105.7 (61.4, NA) 0.0009 8/15 87.3 (47.4, NA) 0.0002 6-month PSA ≥0.2 22/25 43.2 (23.5, 66.0) 25/26 22.1 (13.9, 39.4) Metach LV6-month PSA <0.2 18/34 101.5 (58.6, NA) 0.04 11/38 123.4 (123.4,141.5) 0.003 6-month PSA ≥0.2 17/21 63.6 (49.7, 99.3) 14/26 48.9 (25.6, NA)

Supplementary Figure S2. Comparison of percentage changes in patients’ plasma levels of erythropoietin between baseline and cycle 3 day 1 (A) with respect to their BOR and (B) against the change in hemoglobin levels. Statistical comparison was performed using a two-sample t-test; p < 0.05 was considered significant. Boxplot (Figure A): central line in the box, median; box, interquartile range (IQR; 25th to 75th percentile); whiskers, smallest and largest values within 1.5 times the IQR from the lower and upper quartiles; individual points beyond the whiskers, outliers. BOR, best overall response; PD, progressive disease; PR, partial response; QD, once daily; QW, once weekly; SD, stable disease.

199 Background: Approximately 25% of patients (pts) with prostate cancer have deleterious germline/somatic homologous recombination repair mutations (HRRm). BRCAAway found the combination of an androgen receptor (AR) pathway inhibitor (ARPi) and poly(ADP-ribose) polymerase inhibitor (PARPi) as first-line therapy in pts with mCRPC and BRCA1/2 and/or ATM alterations to demonstrate longer progression-free survival (PFS) vs either agent alone or sequentially. Understanding AR signaling in HRRm (BRCA2 altered especially) versus intact patients and how they relate to response is unknown and may offer insights to mechanisms of resistance/sensitivity. Methods: Pts were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi + Ola). Internally analyzed, pooled circulating tumor cells (CTCs) were captured via bead-based EPCAM antibody with subsequent RT-PCR for gene expression profiling. Pretreatment samples from 47 pts across the three arms were compared to a historical CRPC cohort for difference and evaluated for a predictor of poor PSA response (stable PSA or progression by PCWG3). Results: A high probability of CTCs was found in 23 of 47 pts (48.9%, 11 Abi, 6 Ola, 6 Abi + Ola). In comparison to historical mCRPC pts, those with HRRm did not segregate from DNA repair intact pts regarding AR signaling. Also, PSA responders did not segregate from non-responders. Focusing on those with BRCA2 HRRm (20/23, 10 Abi, 5 Ola, 5 Abi+Ola), lack of PSA response was seen in 6/20 (30%). Combining the monotherapy cohorts, higher AR expression (median 22 for nonresponders and 15 for responders) correlated with lack of PSA response (unpaired t-test p=0.03), while ARV7 (median 18 vs 12) did not but may suffer from underpowering (p=0.20). Interestingly, the Abi+Ola cohort had a median AR expression closer to nonresponders (21.3), yet all 5 responded. Conclusions: Enriched CTC gene profiles from BRCAAway study pts prior to therapy in all arms appear similar to non HRRm mutant pts, supporting that the AR signaling pathway is consistently altered in mCRPC regardless of HRR status. For those with BRCA2 related HRRm, high AR expression associates with poor monotherapy response (Abi or Ola), but not the combination (Abi+Ola), suggesting the combination may rescue patients with AR addiction. Clinical trial information: NCT03012321 . BRCA2 cohort only (n=20) PSA ResponderMedian Gene Expression (IQR 25th/75th ) PSA NonResponder Median Gene Expression (IQR 25th/75th ) Unpaired t-test Monotherapy Cohort (Abi or Ola, n=15) AR 15.0 (13.7, 21.0) 22.0 (20.3, 23.2) P=0.03 ARV7 12.0 (3.8, 16) 18.0 (13.1, 19.7) P=0.20 Combination Cohort (Abi+Ola, n=5) AR 21.3 (20.3, 22.7) None N/A ARV7 16.3 (1.8, 18.0) None N/A

Supplemental Figure 2. Outcomes for primary and exploratory arms.

19 Background: Deleterious germline or somatic HRRm are present in about 20% of mCRPC patients (pts). Preclinically, PARP-inhibition demonstrated synergism with AR-targeted therapy. BRCAAway is a biomarker pre-selected, multicenter, randomized, phase-2 trial which evaluated efficacy of AR-inhibitor (i) vs PARPi vs combination in first-line mCRPC pts with germline and/or somatic mutations in BRCA1/2 or ATM. Methods: Eligibility required front-line mCRPC with no prior exposure to PARPi, ARi, or chemotherapy for mCRPC, and washout of antiandrogen, radiation, and other investigational agents. Eligible pts underwent tumor next-generation sequencing (NGS)/germline testing; pts with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm I abiraterone (1000 mg qd) + prednisone (5mg bid), Arm II olaparib (300 mg bid), or Arm III olaparib + abiraterone/prednisone. Primary endpoint was progression free survival (PFS) as per RECIST 1.1, PCWG3, clinical assessment, or death. Secondary endpoints included measurable disease response rate (RR), PSA RR, and toxicity. Arm I and II pts could cross over at progression. Results: 165 eligible pts were registered and underwent NGS/germline testing; 61 pts with HRRm were randomized to Arms I-III. Median age: 67 years (range 42-85); 55 White, 6 Black; prior Docetaxel 26% for mHSPC, Darolutamide/Enzalutamide 3.3% for nmCRPC; disease sites: bone n=44, viscera n=12, lymph node n=31, other n=3; median baseline PSA: 14 ng/ml (range 0.15-4,037 ng/ml). HRRm status: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n=1 (33 germline, 28 somatic). Median (range) time from randomization to last encounter in pts still alive n=56: 16 (0.8-60), 15 (4.1-36), and 23 (2.9-56) months (m) in Arms I, II and III, respectively. 51 pts had treatment-related AEs; most common Grade 3: fatigue n=3, anemia n=2, and ALT increases n=2. OS is not mature enough with 3 deaths in Arm I and 2 in Arm II. Efficacy results for Arms I-III are presented in the table. At progression 8/19 pts crossed over from abiraterone to olaparib and 8/21 pts vice versa. Median (95% CI) PFS from crossover to: olaparib 8.3 m (5.5, 15), abiraterone 7.2 m (2.8, NR). Median (95% CI) PFS from randomization: olaparib 16 m (7.8-25) and abiraterone 16 m (11-28). RR to crossover treatment: olaparib 38% and abiraterone 25%. PSA RR to crossover treatment: olaparib 50% and abiraterone 63%. Conclusions: In mCRPC pts with BRCA1/2 or ATM alterations, abiraterone/prednisone + olaparib was well tolerated and resulted in a longer PFS vs either agent alone or sequentially. Clinical trial information: NCT03012321 . [Table: see text]

Supplemental Table 4. Patient Demographics.

Supplementary Figure S2. PFS, 1.00 mg/kg vs Total Study Population and CPIExposed Population (Parts A, B, and C, FAS)

Supplemental Table 2. SAEs per arm.