BACKGROUND:The potential impact of treatment sequencing in chemoimmunotherapy combinations remains underexplored. We evaluated 2 alternative dosing schedules of chemotherapy (cisplatin and gemcitabine [GC]) and an immune checkpoint inhibitor (CPI; atezolizumab [A]) for metastatic urothelial carcinoma (mUC). METHODS:This multicenter phase II study randomized cisplatin-eligible patients with previously untreated mUC in a 1:1 ratio. The chemo-first schedule included 2 cycles of GC, followed by 4 cycles of GC + A and A maintenance. The CPI-first schedule originally included a two-cycle A lead-in, later amended to a one-cycle lead-in, followed by 6 cycles of GC + A and A maintenance. The primary endpoint was objective response rate after the protocol amendment. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS:Overall, 31 patients were randomized between 9/2017 and 2/2021 (chemo-first, n = 15; CPI-first, n = 16), with early discontinuation due to the evolving mUC management paradigm. Among the per-protocol evaluable patients (n = 19), ORR was 44% (95% CI, 14%-79%) in the chemo-first schedule and 40% (95% CI, 12%-74%) in the CPI-first amended schedule, with neither arm meeting the predefined efficacy threshold. Median follow-up was 60 months (95% CI 48-not reached [NR]). Median progression-free survival and overall survival (95% CI) were: chemo-first, 6.1 (4.4-NR) and 15 (10-NR) months; CPI-first original, 1.3 (1.1-NR) and 12 (8.4-NR) months; and CPI-first amended, 7.6 (2.0-NR) and 26 (3.6-NR) months. No new safety signals or treatment-related deaths occurred. CONCLUSIONS:This study evaluating the impact of chemotherapy and CPI dosing sequence in patients with mUC was limited by a small sample size and early discontinuation, with neither arm meeting the primary endpoint. Exploratory observations highlight CPI lead-in duration as a potential consideration for future trial design.

Introduction Masofaniten (EPI-7386) is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription, even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants, as a strategy to inhibit prostate cancer growth. In the Phase 1a dose-escalation study (NCT04421222), treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily pretreated mCRPC. We report here the results of the Phase 1b dose expansion first-in-human trial of EPI-7386 in mCRPC. Methods This Phase 1b, open-label, multicenter, dose expansion trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogens. Two cohorts were tested, examining the 600 mg BID and 600 mg QD dosing regimens. Circulating Tumor DNA (ctDNA) samples were also collected in the study at baseline and at cycle 4 to characterize the tumor genomic profile and quantify molecular response. Results 12 pts were enrolled in the 600 mg BID cohort (median follow up 12 months) and 12 in the 600 mg QD cohort (median follow up 8 months). Pts in both arms had a median of 2 (range 1-3) lines of prior therapy for mCRPC: 71% in both cohorts received abiraterone and at least one second generation AR inhibitor (enzalutamide, darolutamide or apalutamide). EPI-7386 was safe and well tolerated at both dosing schedules. The majority of related adverse events (AEs) were grade 1 (47%), and grade 2 (41%). AEs were consistent with AEs associated with second-generation antiandrogens (i.e. anemia, fatigue and hypertension), and no differences were observed between EPI-7386 600 mg QD and BID dosing. As expected, 600 mg BID dosing resulted in higher PK parameters at steady state, with a mean AUC0-24 of 357,000 hr*ng/mL and a mean Clast of 14,500 ng/mL, in comparison to a mean AUC0-24 of 246,000 hr*ng/mL and a mean Clast of 7,120 ng/mL for the 600 mg QD cohort. Both dosing regimens resulted in exposures in the range of those associated with antitumor activity in preclinical models. Evidence of antitumor activity was observed in ∼1/3 of the patients in both cohorts. Notably, genomic characterization of ctDNA samples showed, beside the expected alterations in the AR pathway (AR mutations, amplifications, structural rearrangements), additional molecular alterations associated with disease aggression and lineage plasticity (P53 mut, PTEN deletion, RB1 deletion). Conclusions Data from the Phase 1 dose expansion portion of the first-in-human study with EPI-7386 monotherapy confirmed the favorable safety and tolerability profile of the drug together with the achievement of clinically relevant exposures by both doses/regimens tested. Clinically relevant anti-tumor activity was observed in both arms in a small subset of patients displaying fewer molecular alterations outside of the AR pathway. Based on these observations, the clinical development of masofaniten is now focusing on its combination with other AR pathway inhibitors (NCT05075577; NCT05295927; NCT06312670) in earlier lines of treatment for mCRPC in combination with standard of care AR inhibitors.

TPS243 Background: DARO, a structurally distinct and highly potent androgen receptor inhibitor, has low blood–brain barrier (BBB) penetration and limited potential for drug–drug interactions. In phase 3 trials, DARO showed significant efficacy and a favorable safety profile. In ARAMIS (NCT02200614), DARO and androgen-deprivation therapy (ADT) significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT in pts with nonmetastatic castration-resistant prostate cancer. In ARASENS (NCT02799602), DARO + ADT + docetaxel significantly improved OS in pts with metastatic hormone-sensitive prostate cancer vs placebo + ADT + docetaxel. In both studies, the incidence of adverse events (AEs) was similar between treatment groups. Currently, the ARASTEP study (NCT05794906) is evaluating DARO and ADT in pts with high-risk BCR following primary therapy who have prostate-specific membrane antigen PET/CT-positive lesions. Based on a neuroimaging study of healthy volunteers, cerebral blood flow was not altered with DARO but was significantly reduced in brain areas related to cognition with ENZA. It is postulated that the low BBB penetration of DARO may result in lower serum testosterone elevations than those seen with ENZA, which may reduce the frequency of AEs. The ARAMON study (NCT05526248) will compare the effect of DARO and ENZA monotherapy on post-treatment testosterone levels in pts with CSPC who developed a BCR after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of pts with histologically or cytologically confirmed adenocarcinoma of the prostate who experienced BCR after radical primary prostatectomy (RP) or radiation therapy (RT), with <5 asymptomatic oligometastatic disease sites. Key inclusion criteria are prostate-specific antigen (PSA) ≥2 ng/mL, PSA doubling time of ≤20 months, serum testosterone >150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During the lead-in phase, 25 pts will receive DARO 600 mg twice daily for 52 weeks. If serum testosterone criteria are met at 12 weeks, the study will proceed to the randomized phase where approximately 40 pts will be randomized 1:1 to DARO (600 mg twice daily) or ENZA (160 mg once daily) for 52 weeks. The primary endpoint is the change in serum testosterone level from baseline to Week 12. Secondary endpoints include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of endocrine, glycemic, and lipid metabolism markers; incidence of AEs; and quality of life. As of September 2023, 23 of 25 planned pts in the lead-in phase have been enrolled. Clinical trial information: NCT05526248 .

TPS5118 Background: Novel androgen receptor pathway inhibitors (ARPIs) improve overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in conjunction with testosterone suppression (TS) relative to TS alone. However, the duration of treatment required to derive clinical benefit is unclear, as is whether continuous treatment is requisite for optimal cancer outcomes. Favorable PSA declines have been associated with prolonged OS in clinical trials testing TS + ARPIs. We thus designed this single-arm Phase 2 trial to test the hypothesis that pts who achieve exceptional response to upfront TS + ARPI can suspend treatment, allowing for T recovery and improvement in quality of life while maintaining favorable clinical outcomes. Methods: Eligible pts had mHSPC by conventional imaging with PSA ≥ 5 ng/ml and T ≥ 150 ng/dl (or not known to have been hypogonadal) prior to starting treatment, have been receiving TS for 540-750 days and ARPI for ≥ 360 days, and have achieved PSA < 0.2 ng/ml (stable or falling for 3 consecutive measurements) with castrate T <50 ng/dl at the time of enrollment. Intermittent ADT for biochemical recurrence prior to mHSPC diagnosis, prior local therapy, prior radiation to metastatic sites, and up to 6 cycles of docetaxel in mHSPC are permitted. Pts who underwent surgical castration, received ARPI prior to mHSPC diagnosis, or are receiving experimental treatment for mHSPC or participating in a clinical trial that does not allow for TS or ARPI interruption are excluded. After enrollment, pts discontinue both TS and ARPI and are followed with PSA and T levels every 3 months, conventional CT/MRI and bone scan at least every 6 months, and FACT-P questionnaire for patient-reported outcomes every 6 months. Treatment re-initiation triggers are PSA increase to ≥ 5 ng/ml, radiographic change (progressive disease per modified RECIST 1.1 on CT/MRI or unconfirmed progressive disease per PCWG3 on bone scan), or symptoms attributable to prostate cancer. Subsequent management is per physician discretion. The primary endpoint is remaining treatment-free with eugonadal T (> 150 mg/dl) 18 months after the start of treatment interruption, with 75 pts to be enrolled to differentiate 18-month treatment free rates of 0.30 (null hypothesis) and 0.45 (alternative hypothesis). Secondary endpoints include time to eugonadal T, duration off treatment, and changes in patient-reported outcomes. Exploratory endpoints include radiographic progression-free survival, time to next treatment, OS, and correlation of tissue- and blood-based biomarkers with clinical endpoints. The study was activated in July 2022 and accrual is ongoing throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org , Veracyte Inc. Clinical trial information: NCT05241860 .

141 Background: EPI-7386 (masofaniten) is a next-generation aniten that inhibits androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription, irrespective of ligand-binding domain resistance mechanisms. Preclinically, the combination of masofaniten with Enz results in a deeper blockade of the AR pathway and greater antitumor activity than either agent alone. Methods: This is a Phase 1/2 multicenter clinical trial (NCT05075577) enrolling patients (pts) with mCRPC on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy in the metastatic hormone-sensitive setting allowed). P1 examines escalating doses of masofaniten + Enz at 120 or 160 mg QD. Primary and secondary endpoints of P1 evaluate the safety and pharmacokinetics (PK) of masofaniten + Enz when co-administered to establish the recommended P2 combination doses (RP2CDs). P2 is designed as a two arm, 2:1 randomized, open-label trial evaluating the antitumor activity of masofaniten in combination with Enz versus Enz alone; approximately 120 pts will be randomized with masofaniten 600 mg BID + Enz 160 mg QD (n=80) vs single agent Enz at 160 mg QD (n = 40). Results: P1 completed enrollment with 18 pts in 4 cohorts with 16 pts evaluable for efficacy as per protocol. The combination regimen was well tolerated with a safety profile consistent with Enz monotherapy. One grade 3 rash was observed in cohort 4 evaluating masofaniten 600 mg BID + Enz 160 mg QD. PK results demonstrated Enz exposure was not impacted by concomitant administration of masofaniten, allowing testing of the full dose of Enz (160 mg). By contrast, masofaniten exposure was consistently reduced by concomitant administration of Enz (CYP3A4 inducer that metabolizes masofaniten) but remained within the clinically relevant range with the highest exposures and C min observed using masofaniten BID dosing. Although efficacy data are still maturing, to date, response rates were PSA50 88% (14/16 pts), PSA90 69% (11/16 pts) and PSA <0.2 ng/mL 56% (9/16 pts) in evaluable pts, regardless of their previous chemotherapy status. Conclusions: The RP2CD for P2 was established at masofaniten 600 mg BID + Enz 160 mg QD. Updated results, including long term follow-up of the dose escalation patients, and P2 study design, will be presented. Clinical trial information: NCT05075577 .

4581 Background: SG is a TROP-2 directed antibody-drug conjugate (ADC) approved as advanced-line treatment for mUC after platinum-based chemotherapy and a checkpoint inhibitor, based on phase II study (TROPHY-U-01) that demonstrated objective response rate (ORR) of 28%, median progression free survival (PFS) of 5.4 months (mo) and median overall survival (OS) of 10.9 mo. Current guidelines for mUC endorse using SG in post EV setting, more so with the recent FDA approval of EV and pembrolizumab as the new standard of care for 1st line. Data is scarce regarding the efficacy of SG in patients previously treated with EV, as only 10 patients (8.8%) included in TROPHY-U-01 cohort 1 had prior EV exposure. Here, we report real-world clinical outcomes for SG post EV. Methods: This is a single center retrospective cohort of patients with mUC treated with SG after prior exposure to EV. Demographics and clinical data were collected retrospectively by chart review. Clinical response to SG and EV was defined by physician assessment. Cases with objective response to SG per clinical review [complete response (CR) + partial response (PR)] were then confirmed by formal radiological evaluation using RECIST 1.1. PFS and OS defined from start of SG were calculated using the Kaplan-Meier method. Results: 82 patients were identified, median age was 71 years (range 47-83), 70% male and 37% upper tract primary. Lung, bone, liver and brain metastases were present in 67%, 62%, 50% and 13% of patients, respectively. Median prior treatment lines were 3 (range 1-8), 68% of patients received SG directly post EV. Most patients were treated with single agent EV, though 8 patients (10%) received combination of EV + pembrolizumab. PR was confirmed in 8 patients, and none had CR, resulting in an ORR of 10% (95% CI 4.3%, 18.3%). Stable disease (SD) was achieved in 16 patients (20%, 95% CI 11.9%, 30.4%) amounting to disease control rate (DCR = CR+PR+SD) of 30% (95% CI 20.3%, 41.3%). Median PFS was 2.1 mo (95% CI 1.9, 2.5) and median OS was 6.0 mo (95% CI 4.5, 7.0). There was no association between response to EV and ORR, PFS or OS after SG (p>0.8). Sequencing SG directly after EV was associated with improved ORR (p = 0.028) and PFS (HR=0.43, 95% CI 0.21, 0.87, p=0.02, adjusted for tumor location, treatment line and liver metastasis) but not OS. Dose reductions were required upfront in 18%, on treatment in 44% or both in 7%. Prophylactic granulocyte stimulating factor (GCSF) was used in 57 patients (70%), rates of G3-4 neutropenia, anemia and thrombocytopenia were 36%, 36% and 4% respectively. Conclusions: In our large cohort of real-world advanced mUC patients with prior exposure to EV, SG resulted in limited clinical efficacy compared to previous reports. There was an association between SG administration directly after EV and improved clinical outcomes. Further investigations are warranted to explore optimal treatment sequencing.

4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]

179 Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease >90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577 .

177 Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

TPS273 Background: Prostate cancer is a disease of older age, and there is significant overlap with age-related illnesses. Androgens play a critical role in prostate cancer but also have been linked to cardiovascular (CV) disease, metabolic syndrome, bone health, and frailty. ADT is associated with an increased risk of CV events primarily due to increased rates of diabetes, dyslipidemia, and adverse changes in body composition. We assume that prostate cancer and age-related illnesses share biology with therapeutic implications in a subset of men. The ProTrio trial will test the hypothesis that a 16-week digital risk factor modification program will improve 10-year atherosclerotic cardiovascular disease (ASCVD) risk score as compared to usual care in men with potentially lethal prostate cancer receiving ADT. Methods: This single center, open-label, randomized phase II trial is evaluating a 16-week digital risk factor modification program, which includes an exercise prescription (150 minutes of titrated cardiovascular exercise and resistance exercise 2 times a week) with support via a smart phone application (Moving Analytics) and Fitbit, in patients with prostate cancer who are receiving ADT compared to usual care with Fitbit monitoring. Eligible patients are men receiving ADT +/- an androgen signaling inhibitor for at least 3 months prior to enrollment. The study will enroll to two cohorts: (1) distant metastatic disease and (2) biochemically recurrent or regional lymph node disease. Patients will be stratified according to their baseline ASCVD risk score. The primary endpoint is the difference in ASCVD risk score post-intervention. Secondary endpoints include difference in metabolic severity index z-score, PSA velocity, 6-minute walk, 5X Sit-to-Stand, body composition, physical activity measured by Fitbit, and health-related quality of life. Up to 100 patients will be enrolled in each cohort. A clinically relevant improvement in ASCVD score reduction is 2.5%. With 44 men per arm, after 12% dropout, we can detect an improvement of 2.5% vs. 0% at a 2-sided 5% significance level with 80% power assuming a standard deviation (SD) of 4.125%. A sample size adjustment is planned based on the SD of the first cohort to reach 44 patients. Each cohort will undergo futility analysis once half the men are enrolled. The study is enrolling at MD Anderson Cancer Center. Clinical trial information: NCT05054296 .

TPS5111 Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration. In the phase 3 ARAMIS study (NCT02200614) of patients with nonmetastatic castration-resistant prostate cancer, treatment with darolutamide significantly improved metastasis-free survival and overall survival versus placebo, with a favorable safety profile. The incidences of central nervous system adverse events (AEs; e.g. falls, memory impairment, and depression) showed a ≤2% difference between the darolutamide and placebo groups. Fatigue was the only AE with an incidence of > 10% for darolutamide (13.2% vs 8.3% for placebo). In a separate neuroimaging study of healthy volunteers, cerebral blood flow was not altered in patients treated with darolutamide but was significantly reduced in brain areas related to cognition in patients treated with enzalutamide. Furthermore, it is postulated that the low blood–brain barrier penetration of darolutamide may result in lower serum testosterone elevations than those seen with enzalutamide, with the potential of leading to fewer associated feminizing AEs. The objective of ARAMON (NCT05526248) is to compare the effect of darolutamide and enzalutamide monotherapy on post-treatment testosterone levels in patients with hormone-naive prostate cancer experiencing biochemical recurrence after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of patients with histologically or cytologically confirmed adenocarcinoma of the prostate who have biochemical recurrence after radical primary prostatectomy or radiation therapy, with a prostate-specific antigen (PSA) doubling time of ≤20 months, baseline serum testosterone > 150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During a 52-week lead-in phase, 25 patients will receive darolutamide 600 mg twice daily. If criteria based on serum testosterone increase from baseline to Week 12 are met, the study will proceed to a 52-week randomized phase in which the effects of darolutamide (600 mg twice daily, n = 20) will be compared with the effects of enzalutamide (160 mg once daily, n = 20). The primary endpoint of both phases is the change in serum testosterone level from baseline to Week 12. Secondary endpoints of the randomized phase include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of markers for glucose, lipid metabolism, and endocrine function related to sex hormones; safety; and quality of life. Safety will be assessed through AE monitoring. The first of the 25 planned patients in the lead-in phase was enrolled on January 13, 2023. Clinical trial information: NCT05526248 .

EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription despite resistance driven by point mutations and splice variants in the ligand-binding domain. In preclinical models, the combination of EPI-7386 with Enz results in a deeper blockade of the AR pathway and greater antitumor activity, prompting this trial. This phase I/II multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC patients on androgen deprivation therapy and naïve to second-generation antiandrogens (1 line of prior chemotherapy in the metastatic hormone sensitive setting allowed). PI examines escalating doses of EPI-7386 with Enz. Primary and secondary endpoints of PI evaluate the safety and pharmacokinetics (PK) of EPI-7386 and Enz when co-administered to establish recommended phase II combination doses (RP2CDs) and address possible drug-drug interactions (DDIs). Once RP2CDs are established, phase II (PII) will commence as a two arm, 2:1 randomized trial evaluating antitumor activity of EPI-7386 in combination with Enz versus Enz alone. To date, 11 patients have been enrolled in cohorts 1-3 (cohort 4 is currently enrolling). Safety is consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrate Enz exposure is minimally impacted by EPI-7386, allowing testing of the full dose of Enz (160 mg) in the current cohort 4. EPI-7386 exposure is strongly reduced by Enz (CYP3A4 inducer that metabolizes EPI-7386) but remains in the clinically relevant range seen in xenograft studies. EPI-7386 BID dosing shows an increase in EPI-7386 exposure and mitigates DDI caused by Enz. Data from the first 10 evaluable patients show 9/10 achieve a PSA90, and 7/10 patients reach PSA <0.2 ng/mL. With no safety concerns from cohorts 1-3, cohort 4 is currently enrolling at EPI-7386 BID + 160 mg QD Enz to evaluate optimal RP2Ds before the P2 component of the trial. Updated results, including cohort 4, will be presented.

PURPOSE:To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS:Patients had advanced non-clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS:A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION:Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.

458 Background: Enfortumab vedotin (EV) and, for those with FGFR3 mutations (FGFR3+), erdafitinib, are established therapeutic options for refractory advanced urothelial carcinoma. However, optimal sequencing of these agents remains undefined. Here, we report our experience of EV monotherapy with focus on patients (pts) with FGFR3 alterations. Methods: Pts who were treated with EV were identified. Clinical data and outcomes were extracted. Tumor genomic profiles by the MSK-IMPACT assay as part of standard of care were reviewed for FGFR3 and other commonly altered gene mutations and tumor mutation burden (TMB). Progression-free (PFS) and overall survival (OS) were measured from start of EV therapy and compared with unadjusted log-rank test. Results: 89 patients received EV on completed monotherapy studies (n = 37) or as standard of care. Median age was 62 years (IQR: 62 – 78), 71% were male (n = 63), 28% had liver metastases. Distribution per Bellmunt score (0 – 3) was: 12%, 42%, 37% and 9%. For the entire population, PFS and OS were 5.2 and 11.4 months, respectively, with response rate of 52% among 75 evaluable patients. MSK-IMPACT was available for 80 patients. Overall genomic profile was similar to TCGA cohort except for fewer DNA damage response/repair gene alterations – 15% (ERCC2: 2; ATM: 4, BRCA1: 2, BRCA2: 3, RAD51C: 1) and FGFR3+ rate of 33%. Median TMB was 8.9/Mb (IQR: 5.2 – 13.3). Of the 26 FGFR3+ pts, 8 and 1 received an FGFR3 inhibitor (FGFR3i) before and after EV, respectively. 17 pts have not been exposed to FGFR3i; 13 of whom have progressed on EV and 9 died. Compared to FGFR3- pts, FGFR3+ pts with no prior FGFRi had significantly shorter median PFS on EV (2.5 vs. 6.8 months; HR 0.33 [0.14 – 0.80] p < .01) and trend towards shorter median OS (4.9 vs. 14.6 months; HR 0.42 [0.16 – 1.08] p > .05). PFS on EV among FGFR3+ pts with prior FGFR3i exposure was 6.7 months, similar to FGFR3- pts (HR 0.77 [0.30 – 1.96] p = .6). Response rates for FGFR3+ with and without prior FGFRi, and FGFR3- pts on EV were 4/7 (50%), 5/13 (38%) and 29/48 (60%). Conclusions: In this retrospective study, FGFR+ patients who receive EV first appear to have shorter PFS and lower ORR than those who have received prior FGFRi. Prospective studies on the sequence of EV and FGFR3i in FGFR3+ pts are warranted.

e17090 Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.

TPS2088 Background: ICIs have become the therapeutic standard for many cancers but are associated with unique and diverse irAEs that often occur at home. Appropriately timed and specific interventions are critical to recovery. Thus, there is a need to effectively & efficiently monitor in real time pts treated with ICIs. To improve outcomes, we have activated a clinical trial developed to determine the feasibility and safety of an electronically enabled strategy to remotely monitor symptoms and prompt communication that will guide and inform specific patient-driven “course corrections” in response to potential irAEs. Methods: This is an adaptive prospective trial that uses a mobile irAE-specific PRO application we developed to monitor and alert the care team in real time when severe symptoms are reported. In parallel with the mobile symptom collection, serum and urine biomarkers are collected at baseline, first tumor restaging, and upon the development of irAEs. Optional stool microbiome analyses are also performed. To facilitate the generalizability of our inferences, we are using broad inclusion criteria: ECOG performance status ≤3; any line of ICI given as standard of care or as part of therapeutic clinical trials; elderly pts are included. Because the relationship between PROs and irAEs is currently undefined, we designed our trial to use adaptive symptom thresholds that will notify the healthcare team of suspicion for irAEs. The mobile application will use these dynamic thresholds to determine whether or not to alert the healthcare team. The positive and negative predictive value of each symptom for identifying subsequent irAEs will be assessed at scheduled interim analysis time points. The care teams’ responses to the alerts, and all of the clinical outcomes for the pts over time will be collected as part of the trial. The primary goal of the trial is the assessment of the predictive power of the mobile PRO symptom collection in combination with serum and urine markers to identify grade 2 or higher adverse events that require intervention (e.g., dose modifications, hospitalizations, and therapeutic interventions) within two weeks of symptom onset. Effective remote monitoring of irAEs will leverage our understanding of ICI toxicity and empower pts to be effective partners in their care. The trial has currently enrolled 17 pts towards the enrollment target of 100 pts. Clinical trial information: PA19-0095 .