Abstract The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.

Background Lutetium 177 (177Lu) prostate-specific membrane antigen (PSMA)-617 SPECT/CT has demonstrated promise as a response biomarker for 177Lu-PSMA-617 therapy. Purpose To predict overall survival (OS) after enzalutamide plus 177Lu-PSMA-617 using quantitative parameters at 177Lu-PSMA-617 SPECT/CT at 6 weeks, as well as prostate-specific antigen (PSA) response, in participants with metastatic castration-resistant prostate cancer. Materials and Methods This secondary analysis of the multisite prospective ENZA-p trial (August 2020-July 2022) included participants who received enzalutamide plus 177Lu-PSMA-617 (7.5 GBq). SPECT/CT was performed 24 hours after each treatment, and total tumor volume (TTV) and mean standardized uptake value were compared between the first (baseline) and second (6-week) doses. TTV complete response (CR) at SPECT/CT was defined as TTV less than 1 mL at dose 2, and deep PSA response was defined as 90% or greater PSA reduction at dose 2. Relationships between TTV CR and deep PSA response at dose 2 and OS were examined. Results This analysis included 74 men (median age, 71 years [IQR, 66-78 years]). Median follow-up was 33 months (95% CI: 28, 37). Median OS was 31 months (95% CI: 25, 33), and the 2-year survival rate was 70% (95% CI: 58, 79). Median TTV was 236 mL (IQR, 81-688 mL) at baseline and 65 mL (IQR, 12-215 mL) at 6 weeks. Median change in TTV was -57% (IQR, -89% to -38%); 4.1% (three of 74) of participants had an increase in TTV, and 16% (12 of 74) had TTV CR. Deep PSA response was seen in 63% (45 of 71) of participants. The 2-year survival rate with TTV CR was 83% (95% CI: 48, 96), versus 67% (95% CI: 54, 77) without TTV CR (hazard ratio, 0.26 [95% CI: 0.08, 0.85]; log-rank P = .02). The 2-year survival rate was 76% (95% CI: 58, 87) with deep PSA response without TTV CR (log-rank P = .05 vs TTV CR) and 54% (95% CI: 33, 71) with neither deep PSA response nor TTV CR (log-rank P = .003 vs TTV CR). Conclusion TTV CR at 177Lu-PSMA-617 SPECT/CT at 6 weeks was associated with improved OS and may be a valuable tool for treatment personalization with 177Lu-PSMA-617. ClinicalTrials.gov Identifier: NCT04419402 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Galgano and Turner in this issue.

MONETTE study design, Baseline tumor sample and blood samples, DoR, best percentage change from baseline in target lesion size, OS in PD-L1 and CD8/Ki67 biomarker evaluable populations, micrographs of PD-L1 expression and CD8+/Ki67 cells, baseline area of CD8+ T cells, Ki67+ cells, and proliferating CD8+ Ki67 + T cells in the central tumor region, OS in the baseline circulating immune cell biomarker population, longitudinal pharmacodynamic effects on T cells, OS in GDF-15 biomarker population and baseline GDF-15 as a prognostic marker for OS in monotherapy and combination therapy.

TPS5137 Background: B7H3 is highly expressed in various human cancers, including mCRPC, and overexpression is associated with a poor patient prognosis. BNT324/DB-1311 is an investigational B7H3 ADC comprised of a topoisomerase-I-inhibitor-based payload with a cleavable linker and a drug-to-antibody ratio of ~6 that received FDA Fast-Track Designation for previously treated CRPC. A phase 1/2 study (DB-1311-O-1001, NCT05914116) is currently enrolling several prostate cancer cohorts: post Lutetium-177 [¹⁷⁷Lu]-PSMA-617 radioligand (RLT) (Lu 177-RLT) mCRPC, taxane-naïve mCPRC, and castration-sensitive prostate cancer (CSPC) with suboptimal PSA response, with patients receiving BNT324/DB-1311 alone or with abiraterone or enzalutamide. This study has reported encouraging activity (median radiographic PFS 11.3 months) and a manageable safety profile in heavily pretreated mCRPC (Parsonson A, ASCO 2025 #5015), and in Lu 177-RLT pretreated mCRPC (Stein M, ASCO GU 2026 #176). The treatment landscape of mCRPC has been evolving. As first use of an androgen receptor pathway inhibitor (ARPI) has shifted to the mCSPC setting, more patients will receive docetaxel in early-line mCRPC. The use of Lu 177-RLT in taxane-naïve mCRPC has been increasing; however, outcomes with subsequent docetaxel appear suboptimal. Docetaxel remains the first-line treatment option for symptomatic or rapidly progressive mCRPC, but outcomes are poor. Overall, there is a high unmet need for novel effective and better tolerated treatment options in the post-ARPI and emerging post-RLT settings. Methods: BNT324-03 is an open-label, randomized, Phase 3 trial (NCT07365995) designed to determine the efficacy and safety of BNT324 compared with docetaxel in patients ( > 18 years, ECOG PS 0–1) with mCRPC previously treated with 1 or 2 prior ARPIs. Patients may have received prior Lu 177-RLT but must not have received prior taxane for mCRPC (allowed in mCSPC if ≥6 months since completion without disease progression). Prior treatment with B7H3 targeted therapy is not allowed. Approximately 736 patients will be randomized 1:1 to receive either BNT324 or docetaxel (+ prednisone/prednisolone). Unless there is unacceptable toxicity or withdrawal of consent, BNT324 will be administered until PCWG3-modified RECIST v1.1-defined progressive disease and docetaxel will be administered for up to 10 cycles. Randomization will be stratified by prior Lu 177-RLT, prior taxane use, and site of metastasis. The dual primary endpoints are to assess the efficacy of BNT324 in terms of radiographic PFS and OS when compared with docetaxel. Secondary endpoints include time to first subsequent therapy, ORR and DOR by BICR, time to pain progression, time to first symptomatic skeletal-related event, PSA response and time to PSA progression, and safety. Enrollment is ongoing globally. Clinical trial information: NCT07365995 .

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We demonstrate multiple DC defects in patients with brain tumors. This includes a profound reduction in the frequency of multiple DC subsets, diminished activation marker expression, and reduced Flt3L levels in cancer patients with brain tumors compared to those without. We also demonstrate reduced intra-tumoral DCs in brain compared to lung tumors. This is the first time DC subsets have been fully characterized in a range of brain tumor patients. Importantly, corticosteroid usage was closely associated with DC defects, highlighting the adverse effects of a standard symptomatic treatment on these critical immune cells. However, tumors located within the brain also directly contribute to DC defects. Finally, we identified several mouse brain tumor models that replicate key observations in patients and may be used to further understand this endogenous DC deficiency and to develop approaches to restore DCs, ultimately leading to new combination immunotherapies for the treatment of brain cancers.

TPS2666 Background: Interleukin-2 (IL-2) has antitumor activity through stimulation of proliferation and differentiation of cytotoxic T lymphocytes, but toxicity due to systemic immune system activation limits its clinical use. AZD6750 comprises two CD8 human IgG1 binding domains and two IL-2 mutein domains and uses cis-guiding to deliver IL-2 mutein preferentially to CD8+ T cells, with the goal of increasing antitumor activity while limiting toxicity. It has high affinity for CD8α and the CD122/CD132 IL-2R complex, and reduced affinity for CD25 (IL-2Rα). In preclinical studies, AZD6750 has been shown to cause preferential proliferation of CD8+ T cells without increasing cytokine release from peripheral blood mononuclear cells; improve antigen-specific tumor cytolysis; increase IFN-γ secretion, a sign of productive responses in tumor-infiltrating lymphocytes; and inhibit growth of a tumor model in vivo. We describe the design of a phase I/II trial of AZD6750 in patients with metastatic solid tumors (NCT07115043). Methods: This first-in-human, open-label, phase I/II, multicenter clinical trial is evaluating AZD6750 as monotherapy (Module 1, dose escalation) and combined with rilvegostomig (Module 2) in patients with selected locally advanced or metastatic solid tumors. All patients must have ECOG performance status of 0/1 and ≥1 measurable lesion per RECIST v1.1. In Module 1, patients must have received prior standard-of-care therapy and have a tumor type for which immune checkpoint inhibitors are known to be effective or in which IL-2 potentially has benefit. Dose escalation starts with an accelerated titration design and switches to a modified toxicity probability interval-2 (MTPI-2) design after the first 2 dose cohorts or earlier sign of grade ≥2 toxicity. Module 2 will enroll patients with stage IV NSCLC who have either received ≥1 line of therapy in the metastatic setting (including targeted therapy if actionable mutations are present) (Module 2A, dose escalation) or are metastatic treatment naïve and have tumor PD-L1 expression ≥1% (Modules 2A and 2B). Patients who have autoimmune or inflammatory disorders within 3 years of study or toxicity that led to discontinuation of prior immunotherapy are not eligible for Module 2. In Module 2A, dose escalation will use MTPI-2. Module 2B will be a dose expansion module. The primary endpoints of Modules 1 and 2A are the incidence of adverse events (AEs), serious AEs, and dose-limiting toxicities, which will be used to determine the maximum tolerated dose/recommended phase 2 dose. In Module 2B (dose expansion), the primary endpoint will be preliminary antitumor activity. Secondary endpoints include pharmacodynamics (PD-L1), immunogenicity (anti-drug antibodies), and pharmacokinetics. The study is actively recruiting globally, with 3 patients enrolled as of December 2025. Clinical trial information: NCT07115043 .

CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants among 4,535 tested (0.1%). All had CDK12-driven cancers defined by an additional somatic CDK12 variant and the CDK12-specific hallmark genomic instability signature characterized by hundreds of tandem duplications. Two patients had multiple independent CDK12-driven tumors with distinct secondary somatic CDK12 variants. Germline CDK12 truncating variants were enriched in mPCa compared to gnomAD V4.1.0 controls (n=807,162; odds ratio 11.4, 95% CI 3.6-27.8) and V2.1.1 non-cancer controls (n=134,187; odds ratio 29.6; 95% CI 6.8-28.6). Family history revealed multiple related individuals with prostate or ovarian cancer, and germline variant inheritance was confirmed in the two tested pedigrees. Our data suggest that germline CDK12 truncating variants are a rare driver of lethal mPCa.

BACKGROUND AND OBJECTIVE:ENZAMET randomised 1125 participants with metastatic hormone-sensitive prostate cancer to receive enzalutamide or a standard nonsteroidal antiandrogen (NSAA) combined with testosterone suppression with or without docetaxel. Enzalutamide demonstrated superior progression-free and overall survival (OS). Radiographic progression without prior/concurrent prostate-specific antigen progression (discordant progression; DP) portends poor outcomes. Our aim was to determine the frequency of DP in ENZAMET and the impact of enzalutamide on disease-state transitions. METHODS:A multistate Cox proportional-hazards regression model was used to partition participants into four states: (1) event-free; (2) discordant progression (DP); (3) other types of progression (other progression; OP); and (4) death. KEY FINDINGS AND LIMITATIONS:Enzalutamide prolonged OS in the entire cohort of 1125 participants (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58-0.84; p < 0.0001). Radiographic progression occurred in 388/1125 (34%) participants, and DP in 114/1125 (10%), with similar proportions in the enzalutamide arm (55/114, 48%) and NSAA arm (59/114, 52%). Participant characteristics in the DP group were similar between the treatment arms. Enzalutamide delayed DP (HR 0.66, 95% CI 0.46-0.96; p = 0.03) and OP (HR 0.37, 95% CI 0.31-0.44; p < 0.001). The 5-yr OS rate was lower in the DP group (24%) than in the OP group (42%). Among participants whose cancer had not progressed (495/1125), 51/495 (10%) died of non-prostate cancer causes (median follow-up 68 mo). This exploratory analysis is limited by its post hoc nature. CONCLUSIONS AND CLINICAL IMPLICATIONS:DP occurred in 10% of participants and accounted for 30% of progression events observed in ENZAMET. DP was associated with worse OS regardless of treatment. Enzalutamide delayed DP and reduced the risk of DP and OP. Regularly scheduled imaging may be preferable to for-cause imaging in metastatic hormone-sensitive prostate cancer.

BACKGROUND:Neoadjuvant immune checkpoint inhibitor therapy (nICI) improves outcomes in stage III melanoma. Real-world data remain limited, especially in patient subgroups ineligible for trials or undergoing approaches deviating from trial protocols. METHODS:Retrospective review of all patients who received nICI outside clinical trials for resectable stage IIIB-D melanoma across 8 Australian institutions. Baseline characteristics, treatment details, radiological and pathological responses, event-free survival (EFS) and recurrence-free survival (RFS) were examined. RESULTS:From June 2023 to October 2025, 268 patients received nICI; 173 (65%) had lymph node (LN) metastases only, 65 (24%) had in-transit metastases (ITM) only, and 30 (11%) had both. Anti-PD-1 monotherapy (mono) was used in 198 patients (74%); 70 (26%) received anti-PD-1 + anti-CTLA-4 (combo). Surgery was performed in 227 patients (85%), while 41 (15%) did not proceed to surgery: 25 following clinical complete response (cCR), 14 due to progression, and 2 due to toxicity. Major pathological response (MPR) was achieved in 118 patients (52%). At a median follow-up of 12.1 months, combo was associated with higher 12-month EFS than mono (85.6% vs 75.6%, p < 0.05). Patients with MPR to mono who omitted adjuvant ICI had lower 12-month RFS than those who received it (80.4% vs 100%, p < 0.05); this difference was not observed after MPR to combo. ITM-only patients had similar 12-month EFS to LN-only patients (76.2% vs 81.0%, p = 0.13). No patient managed nonoperatively after cCR recurred. CONCLUSION:Neoadjuvant ICI is feasible in real-world practice, including for ITM-only disease. Following MPR to mono, adjuvant ICI confers superior outcomes than omitting it.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177-Lutetium-PSMA has significantly improved outcomes in advanced prostate cancer; however, optimising its clinical application requires a nuanced, individualised approach. This review outlines key principles for patient selection, therapeutic monitoring, and adaptive dosing strategies to maximise efficacy while limiting toxicity. Adaptive strategies, including dose escalation or fractionation informed by tumour volume, treatment pauces at exceptional response, and retreatment at relapse, offer opportunities to personalise and optimise therapy beyond the standard six-cycle regimen.Additionally, defining clinical, imaging, and molecular biomarkers for resistance and efficacy will improve patient selection and clinical outcomes. As novel radioisotopes and combination strategies emerge, optimising treatment approaches will be essential to realise the full potential of RLT in prostate cancer.

PURPOSE:Clonal hematopoiesis (CH) is a precursor state linked to risk of hematologic neoplasms and may be exacerbated by radiation exposure. We aimed to compare CH prevalence after the new radioligand therapy 177Lu-PSMA-617 versus the alternative standard-of-care cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN:This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free DNA and leukocyte DNA underwent error-corrected deep targeted sequencing. CH mutations were called at variant allele frequency (VAF) ≥0.25%. Variants detected at progression but undetected at baseline were defined as treatment-emergent CH. A total of 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline-progression samples (median interval, 29 vs. 27 weeks). RESULTS:Baseline CH was detected in 77% (138/178) of patients, with similar prevalence and gene distribution between arms. Treatment-emergent CH occurred more often after 177Lu-PSMA-617 than cabazitaxel [62% (37/60) vs. 40% (19/47); P = 0.03], and 83% (121/146) of all emergent mutations were detected after 177Lu-PSMA-617. The DNA damage response gene PPM1D accounted for 42% (51/121) of 177Lu-PSMA-617-emergent mutations, with odds ratios of 3.2 for any treatment-emergent CH and 5.4 for PPM1D, relative to cabazitaxel. CH clones expanded more frequently and to a greater magnitude with 177Lu-PSMA-617 (proportion expanding, 70.9% vs. 29.5%; P = 7.5 × 10-5), and increases in maximal CH VAF correlated with the number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P = 0.002). CONCLUSIONS:177Lu-PSMA-617 strongly promotes CH, supporting integration of longitudinal monitoring for long-term hematologic sequelae as radioligand therapy is implemented earlier in prostate cancer care. See related commentary by Lückerath et al., p. 2527.

BACKGROUND:Lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 improves overall survival and progression-free survival in metastatic castration resistant prostate cancer (mCRPC), whereas immune checkpoint inhibitors (ICIs) have limited activity. Preclinical evidence suggests radioligand therapy might induce immunogenic cell death that can be enhanced with ICIs. This study evaluates the activity and adverse event profile associated with multiple doses of [177Lu]Lu-PSMA-617 with pembrolizumab. METHODS:PRINCE was a multicentre, single-arm, phase 1b/2 trial of [177Lu]Lu-PSMA-617 and pembrolizumab. Eligible participants were aged 18 years or older, had mCRPC, an Eastern Cooperative Oncology Group performance status of 0-1, previous androgen receptor pathway inhibitor therapy with previous docetaxel allowed, and high PSMA expression. Participants received up to six cycles of [177Lu]Lu-PSMA-617 intravenously every 6 weeks with 200 mg of pembrolizumab intravenously every 3 weeks for up to 24 months. Co-primary endpoints were safety and 50% prostate-specific antigen (PSA) response rate. All participants who received treatment were included in the analysis. The trial is registered with ClinicalTrials.gov, NCT03658447, and has been completed. FINDINGS:Between Aug 22, 2019 and Dec 16, 2020, 37 participants (median age 72 years, IQR 67-76; 27 [73%] docetaxel pretreated) received a median of six cycles (IQR 4-6) of [177Lu]Lu-PSMA-617 and a median of 12 cycles (IQR 6-24) of pembrolizumab. Median follow up was 30 months (IQR 28-31). A decline in PSA of 50% or greater from baseline was observed in 28 (76%, 95% CI 59-88) of the 37 participants. Common treatment-related adverse events were grade 1-2. Grade 3 adverse events included anaemia in one (3%) participant and immune-related adverse events in 11 (30%) participants, including two cases each of fatigue (5%), colitis (5%), and increased serum amylase (5%), and one case (3%) each of pancreatitis, pneumonitis, type 1 diabetes, nephritis, myasthenia gravis, and mucosal pemphigus attributable to pembrolizumab. One participant had co-occurring myasthenia gravis and colitis. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION:Multicycle [177Lu]Lu-PSMA-617 and pembrolizumab showed encouraging activity with manageable toxicity that was consistent with [177Lu]Lu-PSMA-617 or pembrolizumab, and the combination might provide durable clinical benefit in a subset of patients. FUNDING:Victorian Cancer Agency, Merck Sharp & Dohme, and Novartis.

Over a period of 10 y, our center treated 766 patients with prostate cancer using 177Lu-PSMA (177Lu-PSMA-617 or 177Lu-PSMA I&T). We report 5 cases of 177Lu-PSMA-induced thrombotic microangiopathy (TMA). Methods: In this retrospective analysis, we reviewed data from all patients at our center who developed histologically confirmed renal TMA after 177Lu-PSMA. Clinical, biochemical, and treatment details were summarized descriptively. Results: TMA occurred 9-20 mo after initiating 177Lu-PSMA therapy. Four patients had a normal baseline estimated glomerular filtration rate (>90 mL/min/1.73 m2). All patients developed progressive renal impairment with biopsy-proven chronic TMA. Glomerular endothelial PSMA expression was observed in 2 of 3 cases, suggesting a potential on-target mechanism of injury via an increased cumulative organ dose of 177Lu-PSMA. The cumulative renal absorbed dose ranged from 38.6 to 65.3 Gy, and the renal absorbed dose per cycle ranged from 5.4 to 12.4 Gy. Two patients received complement inhibition with eculizumab, which improved hematologic features without meaningful renal recovery. Conclusion: 177Lu-PSMA-associated TMA is a rare but a potentially severe complication of treatment. The contribution of initial versus cumulative renal absorbed dose remains unclear, and early dosimetry may help identify at-risk patients.

PURPOSE:Data suggest that ceralasertib, a potent and selective oral inhibitor of the ataxia-telangiectasia and Rad3-related (ATR) DNA damage response kinase, may overcome resistance to prior immunotherapy. PATIENTS AND METHODS:In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral, or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 7, every 28 days. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted. RESULTS:ORR was 9.3% [95% confidence interval (CI), 4.3-16.9] for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95% CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95% CI, 1.9-3.5) versus 1.9 months [95% CI, 1.9-3.1; hazard ratio (HR), 0.80; 95% CI, 0.54-1.18]; and median OS was 16.0 months [95% CI, 10.5-not calculated (NC)] versus 12.3 months (95% CI, 9.5-NC; HR, 0.81; 95% CI, 0.49-1.37). Both regimens were well tolerated. Exploratory analyses indicated a possible link between higher baseline pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. CONCLUSIONS:Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.

TPS5119 Background: Prostate cancer relies on the androgen receptor (AR) pathway as a key oncogenic driver. BMS-986365 is a heterobifunctional, orally bioavailable ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. Results from the first-in-human phase 1 study showed that BMS-986365 was well tolerated with a manageable safety profile and demonstrated antitumor activity in heavily pretreated patients with metastatic castration resistant prostate cancer (mCRPC) regardless of AR gene alterations (Rathkopf et al. Ann Oncol 2025;36:76–88). Here, we present the study design of rechARge (NCT06764485), a phase 3, 2-part, randomized, open-label trial evaluating the efficacy and safety of BMS-986365 versus investigator’s choice of AR pathway inhibitor (ARPI) or docetaxel, in patients with mCRPC who have failed treatment with 1 prior ARPI. Methods: Approximately 960 patients will be randomized in this phase 3, 2-part study. In Part 1 (dose selection), patients will be randomized 1:1:1 to receive either BMS-986365 400 or 300 mg BID Q28D, or investigator’s choice comprising ARPI (enzalutamide [160 mg QD] or abiraterone [1000 mg QD + prednisone] Q28D); or docetaxel 75 mg/m 2 + prednisone Q21D up to a maximum of 10 cycles. In Part 2, patients will be randomized 1:1 to receive either BMS-986365 (dose determined from Part 1) or investigator’s choice treatment (same as Part 1). Randomization is stratified by prior type of ARPI and investigator’s choice (2 nd ARPI vs docetaxel). Patients will be treated until radiographic progressive disease by blinded independent central review (BICR) or unacceptable toxicity; all patients must continue androgen deprivation therapy as part of the standard of care. Key inclusion criteria include no more than 1 previous ARPI, confirmed progressive mCRPC defined by having ≥1 of the following: prostate-specific antigen (PSA) progression or radiographic disease progression in soft tissue based on RECIST 1.1 criteria or bone defined as the appearance of ≥2 new lesions on a bone scan; ECOG PS of 0–1, asymptomatic or mildly symptomatic from prostate cancer (Brief Pain Inventory-Short Form, worst pain in last 24 hr <4), no liver metastases, and no prior chemotherapy in the mCRPC setting (docetaxel permitted for mCSPC if >12 months since completion). The primary endpoint is radiographic progression-free survival by BICR using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. The key secondary endpoint is overall survival. Other secondary endpoints include safety, overall response rate, confirmed PSA response rate (PSA30 and PSA50), and patient reported outcomes. The study is recruiting at 230 sites in 24 countries/territories across North America, Europe, Latin America, and East Asia. Clinical trial information: NCT06764485 .

TPS5136 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with high morbidity and a median overall survival of 2 years. Human kallikrein 2 (KLK2) is highly and specifically expressed in normal and malignant prostate tissue, including late stage mCRPC. Pasritamig is a humanized, IgG1-based bispecific antibody that targets KLK2-expressing cells via CD3 engagement, inducing T cell-mediated targeted cytotoxicity. In a first-in-human study in participants with mCRPC refractory to standard therapies, pasritamig demonstrated a favorable safety profile (< 5% grade 3 or higher treatment-related adverse events and < 10% cytokine release syndrome, all grade 1) and encouraging efficacy at the recommended phase 2 dose with every 6-week (Q6W) outpatient dosing. Methods: KLK2-comPAS is a double-blind, randomized, global phase 3 study to evaluate the safety and efficacy of pasritamig in participants with mCRPC who have previously received all available and suitable life-prolonging therapies including androgen receptor pathway inhibitor, taxane chemotherapy, radioligand therapy (RLT), and poly(ADP-ribose) polymerase inhibitors (for patients with BRCA mutations). Other key inclusion criteria include ECOG performance status 0–2, PSA ≥2 ng/mL, adequate organ function, and ongoing androgen deprivation therapy or prior orchiectomy. Key exclusion criteria include visceral metastases, prior KLK2- or CD3-directed therapies, and active autoimmune disease requiring systemic immunosuppression. Approximately 663 patients will be randomized in a 2:1 ratio to receive pasritamig plus best supportive care (BSC) or placebo plus BSC, stratified by prior PSMA-targeted RLT, number of prior taxanes, and ECOG performance status. BSC may include palliative external beam radiation, low dose steroids, pain medications, bone protective agents, and needed palliative procedures. Pasritamig is administered outpatient at a target dose of 300 mg IV Q6W with two step-up doses of 3.5 mg IV on cycle 1 day 1 and 18 mg IV on cycle 1 day 8. Pre-medications (dexamethasone, diphenhydramine, acetaminophen) will be administered for step-up and first target dose. Participants will receive treatment until confirmed radiographic progression or unequivocal clinical progression, intolerable toxicity, withdrawal, or death. The primary endpoint is overall survival. Key secondary endpoints include radiographic progression-free survival (rPFS), PFS (including clinical progression and unconfirmed bone progression), time to symptomatic progression, and time to skeletal-related events. Enrollment commenced in September 2025 and remains ongoing. Clinical trial information: NCT07164443 .

Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gαq/Gα11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .