Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

BACKGROUND:Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. METHODS:In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. RESULTS:Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0-46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). CONCLUSIONS:Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

TPS293 Background: Advanced mCRPC and metastatic ccRCC are urologic malignancies with poor prognoses, and novel therapies that can improve long-term outcomes remain an unmet medical need. Prostate-specific membrane antigen (PSMA) is a validated therapeutic target for prostate cancer. It is a transmembrane protein with enzymatic activity highly expressed by prostate cancer cells and ccRCC neovasculature. Nezastomig (REGN5678) is a first-in-class, PSMA×CD28 co-stimulatory bispecific antibody (bsAb) that facilitates T-cell mediated tumor killing by bridging PSMA-expressing cells with the costimulatory receptor, CD28, on T cells. Preliminary results have been reported from an open-label, Phase 1/2, first-in-human, multicenter study of nezastomig + cemiplimab in heavily pretreated pts with mCRPC (NCT03972657). In the dose escalation phase, nezastomig (30–300 mg) intravenously (IV) once weekly (QW) + cemiplimab (350 mg) IV once every 3 weeks (Q3W) reduced prostate-specific antigen levels and induced radiographic responses, providing the first evidence of clinical activity with a ×CD28 bsAb in solid tumors. The study has been amended to continue evaluation of nezastomig monotherapy in mCRPC based on the observed clinical activity and possible toxicity from the combination. Nezastomig is also being evaluated in pts with metastatic ccRCC. Methods: Pts with mCRPC must have received ≥2 prior lines of systemic therapy approved for metastatic and/or castration-resistant disease, including a second-generation androgen receptor signaling inhibitor. Pts with metastatic ccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including an anti-programmed cell death-(ligand) 1 therapy and either ipilimumab and/or a tyrosine kinase inhibitor. Nezastomig IV QW monotherapy starting dose for the mCRPC and ccRCC cohorts was informed by tolerability and clinical activity. Dose escalation of nezastomig monotherapy will occur in separate cohorts for mCRPC and ccRCC. When a maximum tolerated dose/presumptive recommended Phase 2 dose is identified, additional expansion cohorts may be evaluated. In pts with progressive disease after ≥6 weeks of nezastomig monotherapy, low-dose cemiplimab IV Q3W may be added. Dose escalation primary objectives are to determine safety, tolerability, and pharmacokinetics of nezastomig. Dose expansion primary objective is to assess efficacy of nezastomig (measured by objective response rate per modified Prostate Cancer Working Group 3 criteria [mCRPC cohorts] and per Response Evaluation Criteria in Solid Tumors version 1.1 [ccRCC cohorts]). The study is open and enrolling; 101 pts (97 with mCRPC; 4 with ccRCC) have been enrolled as of September 12, 2024. Clinical trial information: NCT03972657 .

BACKGROUND:Small cell neuroendocrine prostate cancer (SCNC) is a lethal subset of prostate cancer with limited treatment options. Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP 8/9) triggers the inflammasome to alert and prime immune cells, leading to induction of interleukin (IL)-18 and IL-1ß, bridging innate and adaptive immunity. Talabostat was evaluated in a phase 2 study in combination with pembrolizumab in patients with SCNC. METHODS:Patients were required to have centrally confirmed histologic evidence of de novo or treatment-emergent SCNC and progression on ≥1 prior line of systemic therapy. Patients received pembrolizumab (200 mg intravenous every 21 days) + BXCL701 0.2 mg orally two times per day for a week, with step-up to 0.3 mg two times per day on days 8-14, and 0.3 mg two times per day on days 1-14 of subsequent cycles. The primary endpoint was the composite response rate (CRR). Biomarkers including levels of DPP 8/9 expression and association with clinical outcomes were analyzed in a post hoc fashion. RESULTS:34 patients were enrolled, including 21 (62%) with visceral metastases. Patients had received a median of 3 prior lines of systemic treatment, including 19 (56%) and 18 (53%) of patients who received prior platinum and taxane chemotherapy, respectively. In the response evaluable subset (n=30), the CRR was 20% (95% CI 7.7% to 38.6%) and the objective response rate was 13% (95% CI 3.8% to 30.7%). The median duration of objective response was 9.0 months. All responders had tumors with low tumor mutational burden and/or microsatellite stability. The median radiographic progression-free survival was 2.1 months (95% CI 1.9 to 4.2). The median overall survival (OS) was 13.7 months (95% CI 7.0 to unevaluable) and the 12-month OS rate was 54.1% (95% CI 34.2% to 70.3%). The most frequently occurring treatment-related adverse events of any grade severity were fatigue (41%), hypotension (29%), dizziness (21%), pruritus (24%), nausea (15%), and diarrhea (15%). Baseline levels of DPP9 tumor stromal expression were associated with response. CONCLUSIONS:Talabostat plus pembrolizumab demonstrates preliminary anti-tumor activity in patients with relapsed SCNC. Further evaluation in a randomized study is warranted to assess the contribution of talabostat in this high-risk disease subset. TRIAL REGISTRATION NUMBER:NCT03910660.

136 Background: Androgen deprivation therapy (ADT), used for advanced prostate cancer (PC), has shown mixed associations with dementia in previous studies. We evaluated whether ADT for PC raises the risk of dementia in a large, real-world sample, hypothesizing that patients receiving ADT for PC would have higher odds of dementia compared with PC patients not treated with ADT. Methods: A de-identified open-claims real-world database (NorstellaLinq) included patients age ≥40 years, diagnosed with PC between August 1, 2015, through December 31, 2021, with follow-up data through March 31, 2023. We used target trial emulation, treating the date of PC diagnosis as day 0 and examining whether receiving ADT within 180 days was associated with risk of dementia at ≥365 days. Death was inferred for patients with no claims for ≥12 months. We used competing risk analyses, accounting for death as a competing risk. Covariates included age, presence of metastatic PC, other non-PC cancers, medical comorbidities, and race, derived using an algorithm based on Bayesian Improved Surname Geocoding. Results: Of the 1,495,181 patients who met the study criteria, 9.4% received ADT within 180 days after PC diagnosis; 16% died during the study. Dementia diagnoses after day 365 were observed among 4.2% of ADT recipients and 4.2% of patients not treated with ADT. Using ADT within 180 days after PC diagnosis was not associated with dementia (aHR [adjusted hazard ratio]=0.993, 95% CI 0.97–1.02, p=0.639); ADT was associated with higher adjusted risk of death (aHR=1.268, 95% CI 1.25–1.28, p=3.5e –285 ). Sensitivity analyses found similar results. Compared with White patients, Black (aHR=1.40, 95% CI 1.34–1.46, p=8.9e −54 ) and Hispanic patients (aHR=1.26, 95% CI=1.21–1.32, p=6.7e −23 ) had higher risk of dementia. In analyses examining dementia risk among patients receiving various classes of ADT, patients receiving gonadotropin-releasing hormone agonists had higher risk of dementia (aHR=1.05, 95% CI 1.02–1.090) compared to patients not receiving ADT, and patients who received androgen receptor inhibitors (aHR=0.91, 95% CI 0.86–0.95) or androgen synthesis inhibitors (aHR=0.85, 95% CI 0.77–0.95) had lower risk of dementia than patients not receiving ADT. Conclusions: Contrary to our hypotheses, we found no increased risk of dementia among PC patients treated with ADT compared with those not treated with ADT in this large, real-world sample. However, future studies should further examine the findings of higher dementia risk among Black and Hispanic patients and among patients receiving gonadotropin-releasing hormone agonists.

Importance:Adaptive therapy is an evolution-based treatment paradigm that has been shown to delay resistance in prostate cancer through treatment breaks that control, rather than minimize, tumor burden. However, patient responses are highly heterogeneous, and there is a significant unmet clinical need for biomarkers to personalize treatment scheduling. Objective:To develop and retrospectively validate mathematical biomarkers that predict time to progression (TTP), mean daily dose, and overall survival (OS) under adaptive therapy from first-cycle prostate-specific antigen (PSA) dynamics. Design, Setting, and Participants:This retrospective modeling and validation study used longitudinal, nonrandomized clinical trial data from 2 independent cohorts: 40 patients with castrate-sensitive prostate cancer (CSPC) (June 1996 to September 2006) and 13 patients with metastatic castrate-resistant prostate cancer (mCRPC) (April 2015 to January 2022). A 2-population differential equation model was used to describe the overall tumor growth through the competing dynamics of drug-sensitive and drug-resistant cells. The statistical analysis was conducted from January 2025 to May 2026. Exposures:Patients received either intermittent androgen deprivation therapy (for CSPC) or adaptive abiraterone acetate (for mCRPC). The initial treatment cycle served as the exposure period to extract longitudinal PSA kinetics. Main Outcomes and Measures:Mechanism-based mathematical biomarkers (adaptive therapy score, expected TTP, and expected mean daily dose) were derived from first-cycle PSA kinetics. Outcomes included in silico benchmarking experiments and retrospective validation against clinical TTP and OS. Performance was benchmarked against standard phenomenological PSA metrics (eg, PSA nadir, time to nadir, and doubling time). Results:Overall, data from 53 patients across 2 clinical trials were included. In the CSPC cohort of 40 patients, the adaptive therapy score derived from first-cycle data was highly prognostic for prolonged clinical TTP (univariable hazard ratio [HR], 0.49; 95% CI, 0.31-0.76; P = .002). In the mCRPC cohort of 13 patients, the adaptive therapy score exhibited a strong rank correlation with clinical TTP (Spearman ρ = 0.76; P = .002) and was associated with prolonged TTP (HR, 0.41; 95% CI, 0.16-1.07; P = .07). Analysis of long-term survival data in the mCRPC cohort demonstrated that both the adaptive therapy score and expected TTP were significantly associated with prolonged OS, whereas standard empirical PSA metrics displayed no association with OS. Conclusions and Relevance:In this modeling and validation study, mechanism-based mathematical biomarkers derived from the initial-cycle PSA dynamics accurately predicted patient-specific outcomes and survival, outperforming traditional phenomenological PSA monitoring. These accessible metrics could act as a mathematically informed decision support framework to stratify patients into personalized treatment protocols.

770 Background: Erdafitinib (E), a pan-FGFR inhibitor, is approved for FGFR3-altered mUC after prior therapy. Enfortumab Vedotin (EV) is active as monotherapy post-platinum and in combination with pembrolizumab (EVP) as 1 st line therapy in mUC. Retrospective studies suggest EV activity is maintained in FGFR 3/2-altered disease. Since EV and E have different mechanisms of activity and toxicities are mostly non-overlapping, we evaluated the feasibility, safety, pharmacokinetics (PK), and antitumor activity of E+EV in this population. Methods: Single arm, multicenter Phase Ib with 3+3 dose-escalation and expansion study of E at 8 mg daily orally + EV on days 1,8, and 15 every 4 weeks in FGFR3/2 altered mUC patients who progressed on prior therapies. EV dose level 1 (DL1) was 1 mg/kg, escalation dose was 1.25 mg/kg (DL2), and reduction was allowed to 0.75 mg/kg (DL -1). Primary objective: determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV with fixed dose of E. Secondary objectives: objective response rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and PK. Results: Fifteen patients were enrolled and completed the dose limiting toxicity (DLT) period (1st cycle). Median age was 69 years and 13 (87%) were male. In dose-escalation, 6 patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The MTD and RP2D of EV was 1.25 mg/kg with E at 8 mg/day; an additional 6 patients were treated at RP2D. Common all-grade treatment-related adverse events (TRAEs) included hyperphosphatemia, AST increase, mucositis, diarrhea, fatigue, peripheral neuropathy, dry mouth, palmar–plantar erythrodysesthesia (PPE) and hypercalcemia. Grade 3–4 TRAEs were UTI 27%, PPE 20%, anemia 13%, lymphopenia 13%, vomiting 13%, Stevens–Johnson syndrome 7%, and hyponatremia 7%; there were no grade 5 events. PK: E Ctrough 1320±421 ng/mL. For the EV payload (MMAE), exposures aligned with monotherapy references—DL1: Ctrough 0.6±0.3, Cmax 3.9±0.9 ng/mL; DL2: Ctrough 0.9±0.6, Cmax 5.5±2.3 ng/mL. Objective responses were observed in 14 of 15 patients (93.3%, 95% CI: 68.1-99.8%), including 12 partial responses, 2 complete responses, and 1 stable disease. The median OS was 26.4 months (95% CI 12.1-NR); median PFS was 11.1 months (95% CI: 7.6-NR) with median follow up of 27.2 months (95% CI 18.6- NR). The median DOR was 8.25 months (range 1.7-24.2) among responders. Conclusions: E+EV was feasible, tolerable, and showed high anti-tumor activity in FGFR3/2-altered mUC. The magnitude of response in this small cohort supports a biologic rationale for dual targeting of FGFR3 signaling and NECTIN-4–mediated antibody drug conjugate with further prospective evaluation of EVP and FGFR3-selective inhibitors in larger biomarker-defined studies. Clinical trial information: NCT04963153 .

Background: Androgen deprivation therapy (ADT) is widely used in the management of prostate cancer (PCa) and remains a cornerstone of treatment across multiple disease settings. Although ADT contributes substantially to disease control, it also induces significant adverse metabolic and body composition changes. These alterations include loss of lean mass, increased fat mass, and deterioration in muscle quality, together contributing to a clinical phenotype consistent with sarcopenic obesity (SO). Importantly, ADT-induced SO is characterized not only by reductions in skeletal muscle mass but also by impaired muscle quality, particularly the fatty infiltration of skeletal muscle, or myosteatosis, an underrecognized but defining feature of this syndrome. Methods: This narrative review examines current evidence regarding interventions aimed at mitigating sarcopenic obesity in men treated with ADT for prostate cancer, identifies key gaps in the literature, and proposes a mechanism-driven path forward for intervention development. Results: Several exercise- and nutrition-based interventions have been evaluated in men receiving ADT and demonstrate improvements in selected outcomes such as muscle strength, body composition, and metabolic parameters. However, most studies have been limited by small sample sizes, short intervention durations, and a focus on isolated intervention components. Importantly, muscle quality and intramuscular fat infiltration (myosteatosis), a central component of sarcopenic obesity, have rarely been incorporated as biomarkers or endpoints in intervention trials targeting men receiving ADT. Conclusions: Future interventions designed to mitigate SO and its associated metabolic abnormalities should evaluate comprehensive, bundled strategies initiated early during ADT and sustained long enough to capture clinically meaningful changes. Outcomes should include biomarkers of muscle mass, strength, and quality, including imaging-based measures of myosteatosis, along with metabolic syndrome markers, inflammatory mediators, functional outcomes, adherence, and quality of life. These changes should evaluate the correlation with underlying biological mechanisms such as NF-κB signaling and pro-inflammatory cytokines. Such data may inform future phase III trials and ultimately support clinical strategies to mitigate ADT-related sarcopenic obesity and its downstream cardiometabolic and oncologic consequences.

863 Background: We previously reported that the combination of IPI-NIVO plus SG shows high efficacy with 83.3% objective response rate (ORR) and durable responses as first-line treatment for cisplatin-ineligible mUC patients in a Phase I/II trial. However, two grade 5 immune-mediated myocarditis events attributed to IPI-NIVO occurred, leading to early trial termination after accruing 25 patients. Given the high ORR, we performed correlative analysis to identify a predictive biomarker for response. Methods: For Nanostring GeoMx DSP spatial transcriptomics, 19 baseline tumor samples were evaluable. Patients were categorized as responders (CR+ PR, n=15) and non-responders (SD+ PD, n=4). The raw Nanostring GeoMx probeQC count data was quality-controlled for both segment and gene levels using GeomxTools package in R version 4.3. The segments with flags such as ‘Low Percent Aligned Reads’, ‘Low Percent Stitched Reads’, ‘Low Surface Area’, ‘Low Nuclei Count’, ‘Low Negative Mean’, and ‘Low gene detection rate’ were excluded from further analysis. In total, 35 and 24 segments were left for responder and non-responder groups, respectively. Genes with raw count smaller than the ROI-specific limitation of quantification (LOQ) and low detection rate among segments were excluded from downstream analysis. Totally, 8230 genes were left for 59 segments for further analysis. The differential expression between groups was done using a linear mixed-effect model. Results: 90 and 136 genes were significantly up- and down-regulated in responder group and non-responder group (P value < 0.05 for both). The top upregulated genes in responders included: IGHG2, IGKC, ACKR2, KRT80 and SCD, while those upregulated in non-responders included: S100A2, AKR1C3, MYCN, MAGEA3, and OBSCN (P value < 0.05) . Gene set enrichment analysis (GSEA) revealed gene signatures from B cell-mediated immunity pathway significantly enriched in the responder group (FDR = 0.02), while gene signatures from PRC2_EZH2_UP.V1_DN related to polycomb-mediated transcription reprogramming and promoting tumorigenesis were significantly enriched in the non-responder group (FDR = 0.0017). Trop2 and Topoisomerase 1 genes were upregulated in responders but not statistically significant. Conclusions: Spatial transcriptomics analysis suggests that upregulated B cell-mediated immunity pathways may predict response to combination IPI-NIVO + SG in patients with mUC. The PRC2-EZH2 pathway may represent a potential resistance mechanism and therapeutic target. Transcriptomic evaluation of the therapeutic targets of the antibody and the payload in antibody-drug conjugates warrant further study as predictive biomarkers. Further analyses to identify biomarkers for severe immune events may help optimally select patients for the best therapeutic index. Clinical trial information: NCT04863885 .

145 Background: The phase 3 CONTACT-02 study significantly improved PFS and showed a trend in OS benefit with C+A vs a second novel hormone therapy (NHT) in mCRPC pts with soft tissue metastases (mets). We report outcomes from similar pts in the randomized mCRPC expansion cohorts of COSMIC-021 evaluating the contribution of adding A to C vs C alone. Methods: Pts with mCRPC with extrapelvic visceral or nodal mets who progressed on one prior NHT were randomized to receive C (60 mg QD), A (1200 mg IV Q3W), or C (40 mg QD) + A (1200 mg IV Q3W). Cohort A (n=10) was terminated early (lacked objective responses). The primary and secondary endpoints were investigator-assessed ORR per RECIST v1.1 and safety, respectively. Efficacy outcomes by blinded independent radiology committee (BIRC) were also assessed. Flow cytometry and proteomic profiling were performed on baseline and on-treatment samples. Results: A total of 101 pts were randomized to C (n=51) and C+A (n=50); median age was 70 y in both groups, 75%/72% had bone mets, 20%/24% had liver mets, and 31%/24% received docetaxel for mCSPC. ORR by BIRC (Table) and investigator (C: 20%, 95% CI, 10–33; C+A: 22%, 95% CI, 12–36) were similar between groups. Although PFS by BIRC was similar (Table, HR, 0.96; 95% CI, 0.59–1.58), the KM estimate of pts without events at 12 mo was higher with C+A (25.8% vs 14.0%). Compared with C, C+A group had longer DOR (~2-fold), fewer pts with progressive disease (PD) as best response, a numerically higher median OS (HR, 0.91; 95% CI, 0.57–1.46), more pts with PSA response with longer duration of response (median mo [95% CI], NE [6.24, NE] vs 6.93 [4.63, NE]), and prolonged time to PSA progression (Table). In the liver mets subgroup, median PFS and OS were longer with C+A vs C (PFS: HR, 0.44; 95% CI, 0.15–1.34, 5.7 vs 2.5 mo; OS: HR, 0.25; 95% CI, 0.08–0.77, 14.7 vs 5.0 mo). Grade 3–4 treatment-related adverse events occurred in 51% and 58% in C and C+A, respectively; no grade 5 events occurred. Differential regulation of activated CD8 T cells, myeloid-derived suppressor cells, and immune response and apoptosis-related proteins were observed with C+A vs C or A. Conclusions: C and C+A demonstrated clinical activity in pts with mCRPC and extrapelvic soft tissue mets, with no new safety signals. These exploratory data from randomized cohorts suggest an additive effect of A to C with a prolonged DOR in C+A vs C; additive clinical benefits were noted in pts with liver mets. Clinical trial information: NCT03170960 . Efficacy outcomes by BIRC. C (n=51) C+A (n=50) ORR, % (95% CI) 12 (4–24) 14 (6–27) Complete / partial response, n (%) 0 / 6 (12) 0 / 7 (14) Stable disease / PD, n (%) 33 (65) / 9 (18) 31 (62) / 6 (12) DCR, n (%) 39 (76) 38 (76) Median DOR (95% CI), mo 4.3 (2.8–NE) 10.6 (6.7–NE) PSA response, n (%) 5 (12%) 8 (20%) Median time to PSA progression (95% CI), mo 3.5 (1.7–5.7) 5.6 (2.7–NE) Median PFS, mo 6.7 5.5 Median OS, mo 13.8 15.6 NE, not evaluable for KM estimates.

PURPOSE:We aim to identify biomarkers of progression in an ongoing pilot trial using adaptive dosing in metastatic castrate sensitive prostate cancer (mCSPC). PATIENTS AND METHODS:Men with mCSPC were given combined androgen deprivation therapy with an androgen receptor signaling inhibitor followed by a treatment break after achieving >75% PSA decline. This was followed by evolution-informed drug cycling to prevent resistance outgrowth. Just 6 of 16 patients have progressed at month 55, and we wish to identify predictive features that would help identify these patients. We compare clinical features, testosterone metrics, and PSA metrics over the trial cohort, and we fit a mathematical model to the dynamic patient-specific data to gain more mechanistic insight as to what might be driving early progression. RESULTS:Significant clinical risk factors predicting progression included the risk status, the number of bone metastases, and the total number of metastases. However, analyses of the dynamical changes in PSA and testosterone during the initial cycle of treatment identified several useful features to discriminate early, late, and non-progressors. Specifically, a higher PSA at the end of the induction phase, a lower percent change in PSA over the induction period, and a higher average PSA/Testosterone ratio over the first cycle significantly predicted progressors. Thresholds for these metrics are able to distinguish the earliest progressors. A simple mathematical model coupling the PSA and the testosterone dynamics suggests a higher fraction of resistant cells exist prior to therapy for those that progress earlier. CONCLUSION:PSA/Testosterone ratio is a useful feature to couple drug response to tumor burden dynamics and predict early progression from the first cycle of adaptive therapy.

Movies corresponding to simulation examples in Figure 6, comparing continuous and adaptive therapy for simulations with intermetastasis and intrametastasis heterogeneity.

Figure S8. Evaluation of benefit from elimusertib in patients with specific tumor-associated DDR alterations (A–D)

Initial results from a Phase 1/2 trial (NCT03972657) of the co-stimulatory PSMA×CD28 bsAb nezastomig (REGN5678) plus anti-PD-1 antibody cemiplimab in mCRPC suggested a correlation between clinical activity and high-grade immune-mediated adverse reactions (imARs). Here, we present updated safety and efficacy results, and new survival and biomarker analyses. Pts with mCRPC who had received ≥2 prior lines of systemic therapy, including ≥1 prior second-generation anti-androgen, were enrolled. Dose levels (DLs) of intravenous (IV) nezastomig ranged from 0.1 to 300 mg weekly (QW). Most pts received nezastomig monotherapy for 3 weeks, followed by combination with cemiplimab 350 mg IV every 3 weeks (Q3W) until disease progression or unacceptable toxicity. Primary and secondary endpoints included safety, tolerability, pharmacokinetics, and PSA50 and PSA90 responses. Exploratory endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Biomarker analyses included immune cell phenotyping and cytokine profiling from peripheral blood. At data cutoff (Feb 16, 2024), 78 pts had been treated in combination with cemiplimab. Treatment-related adverse events of any grade occurred in 60 pts (77%); most commonly fatigue (27%), cytokine release syndrome (13%; all G1 except one G2), and nausea (13%). imARs ≥G3 occurred in 11 pts (14%), primarily in pts with PSA50 responses (8/11). All imARs ≥G3 occurred after cemiplimab addition. Two pts (3%) experienced G5 imARs (HLH, hepatitis). Clinical responses were observed exclusively at nezastomig DLs ≥30 mg (n=61), where 15 pts (25%) achieved PSA50 and 10 pts (16%) achieved PSA90. Kaplan-Meier (KM)-estimated median rPFS (95% CI) was 5.0 months (2.1-12.0) at DLs ≥30 mg and 2.1 months (1.9-3.5) at DLs <30 mg. As of an additional data cutoff performed for longer term survival (Jul 19, 2024, median follow-up of 22.7 months [IQR 16.3-36.7]), the KM-estimated median OS (95% CI) was 17.3 months (11.0-not estimable) at DLs ≥30 mg and 10.3 months (3.7-12.6) at DLs <30 mg. Peripheral blood analyses suggest increased T-cell activation and inflammatory signaling following nezastomig plus cemiplimab treatment. Updated results provide further evidence of durable clinical anti-tumor activity in mCRPC at nezastomig DLs 30-300 mg QW combined with cemiplimab 350 mg Q3W. In preliminary analyses, encouraging survival outcomes were observed with the higher nezastomig DLs plus cemiplimab. Anti-tumor responses were tightly associated with high-grade imARs. Exploration of nezastomig dose ranging is ongoing along with additional combination strategies. The mechanism linking clinical anti-tumor activity and toxicity is being investigated. Bilal A. Siddiqui, Jingsong Zhang, Benedito A. Carneiro, Kevin K. Zarrabi, Mark N. Stein, David R. Wise, Edward P. Gelmann, Che-Kai Tsao, Gerald Falchook, Joseph W. Kim, Xin Gao, Przemyslaw W. Twardowski, Divya Rana, Fang Fang, Shilpa Govindraj, Jennifer S. Sims, Dimitris Skokos, Frank A. Seebach, Israel Lowy, Pradeep Thanigaimani, Matthew Ingham, Sabina Sandigursky, Elizabeth Miller. Updated safety and efficacy results from a phase 1/2 study of nezastomig, a first-in-class co-stimulatory PSMA×CD28 bispecific antibody (bsAb), plus cemiplimab (anti-PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT064.

Figure S4. Patient enrollment and disposition in the alternative-schedule dose-escalation cohorts

Figure S6. Best response, earliest time point, duration of best response, previous PARPi exposure, platinum sensitivity, biomarker status, and duration of treatment in the prostate (A, B), colorectal (C, D), and breast (E, F) cancer dose-expansion cohorts, and best response, biomarker status, and duration of treatment in the alternative-schedule dose-escalation cohorts (G–J)