Sridhar, Srikala S

TPS4642 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a Phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, Phase 2/3 trial. In Part A (Phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In Part B (Phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended Phase 3 dose (determined using Part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in Part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in Part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab (<6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of Part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (Part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (Part B). In Part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In Part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

5054 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) versus physician’s choice of docetaxel or an androgen-receptor pathway inhibitor (ARPI) (abiraterone or enzalutamide) in men with BRCA mutations who were chemotherapy-naïve in the mCRPC setting and had received one prior ARPI in the phase 3 TRITON3 trial (NCT02975934). This post-hoc analysis evaluated whether the timing of prior ARPI therapy impacted the efficacy of rucaparib. Methods: Patients were randomized 2:1 to rucaparib (600 mg BID) or physician’s choice of docetaxel or ARPI, after progression on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Outcomes were analyzed according to whether patients received the prior ARPI in the metastatic castration sensitive (mCSPC) or castration resistant (mCRPC) setting. Data cutoff was August 25, 2022. Results: Of the 302 BRCA1/2 patients, 68 received prior ARPI in the mCSPC setting (42 rucaparib; 26 physician’s choice) and 234 in the mCRPC setting (159 rucaparib; 75 physician’s choice). Baseline characteristics were generally similar. Prior treatments in the mCSPC and mCRPC groups, respectively, included abiraterone (73.5% vs 53.0%), enzalutamide (29.4% vs 48.3%), and docetaxel (17.6% vs 24.8%). Median rPFS favored rucaparib over physician’s choice in both groups (mCSPC: 13.6 vs 8.2 months; HR 0.60 [95% CI, 0.32–1.15]; mCRPC: 11.2 vs 5.8 months; HR 0.43 [95% CI, 0.30–0.61]). Median OS was similar between treatments in both settings (mCSPC: 23.2 vs 21.7 months; HR 0.81 [95% CI, 0.47–1.41]; mCRPC: 23.2 vs 21.0 months; HR 0.91 [95% CI, 0.66–1.25]). Treatment-related adverse events occurred at comparable rates (89.6% vs 86.1%). Conclusions: Rucaparib demonstrated efficacy in patients with BRCA-mutated mCRPC, regardless of whether prior ARPI was administered in the mCSPC or mCRPC setting. Clinical trial information: NCT02975934 .

4514 Background: Maintenance avelumab is a standard of care in patients (pts) with la/mUC who do not progress after first-line PBC. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM, active in multiple solid tumors. We hypothesized that an avelumab (Av)-CABO combination would improve outcomes in pts with mUC with an acceptable safety profile compared to avelumab maintenance alone. Methods: MAIN-CAV (NCT05092958) is a phase III randomized, multicenter, international trial for la/mUC pts who did not progress after 4-6 cycles of any PBC (gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC, ddMVAC). Pts were randomized 1:1 to Av 800 mg IV every 2 weeks alone or with CABO 40 mg daily for ≤2 years. Stratification factors were response to first-line PBC (complete response [CR] vs partial response [PR] vs stable disease [SD]) and visceral metastases. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), safety and quality of life. The target accrual was 654 pts; the trial closed early after enrollment of 68 pts following adoption of enfortumab vedotin plus pembrolizumab as the new preferred first-line standard in the US. Results: From 3/2022 to 3/2024, 68 pts were randomized (Av n = 33; CABO-Av n = 35). Median OS was 24.8 months (mo) with Av and 23.0 mo with Avb-CABO (Hazard ratio 1.41; 95% CI 0.66–3.01; p = 0.186). Median PFS was 4.6 mo with Av vs 6.0 mo with Av-CABO (p = 0.343). Objective response rate among pts with PR or SD after first-line PBC was 20.8% with Av vs 11.5% with Av-CABO (p = 0.424). Grade ≥3 treatment-related adverse events occurred in 24.2% pts on the Av arm vs 39.4% of pts on the Av-CABO arm and CABO dose reductions occurred in 63% of pts. Conclusions: Addition of CABO to Av did not improve OS or PFS compared with Av alone in this underpowered, prematurely closed phase III trial; safety was consistent with known profiles. U10CA180821,U10CA180882; U24CA196171, U10CA180863. (CCTG);U10CA180888 (SWOG); https://acknowledgments.alliancefound.org. Clinical trial information: NCT05092958 .

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( < 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

155 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study of rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) in patients with chemotherapy-naive mCRPC and BRCA1/2 (BRCA) vs the control arm of physician’s choice of DTX or ARPI (abiraterone acetate [ABI] or enzalutamide [ENZ]) demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS, primary efficacy endpoint) vs physician’s choice. Here, we report final OS and safety results from TRITON3. Methods: Patients with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI, or ENZ (control). OS was a key secondary endpoint tested initially in the BRCA subgroup, followed by the intent-to-treat (ITT) population in an ordered step-down multiple-comparisons procedure. Crossover from placebo to rucaparib was allowed after radiographic progression was confirmed by independent radiology review. Results: As of March 1, 2024 (final analysis data cutoff),patients with BRCA (N = 302) and ATM (N = 103) alterations were randomized (ITT, N = 405). After an overall median follow-up of 44.0 months, median OS in the BRCA subgroup in the rucaparib arm was 23.2 months vs 21.2 months for the physician’s choice control arm (HR, 0.91 [95% CI, 0.68–1.20]; P = 0.5044; Table). Hierarchical testing did not continue due to lack of statistical significance. No OS benefit was observed in the ITT population or ATM subgroup (Table). Median duration of treatment in rucaparib and physician’s choice arms was 8.3 and 5.1 months, respectively. The most frequent any-grade treatment emergent adverse event (TEAE) in the rucaparib (n = 270) and physician’s choice (n = 130) arms was asthenia/fatigue (61.5% and 63.1%, respectively). The most frequent grade ≥3 TEAE was anemia (23.7%) with rucaparib, and asthenia/fatigue (9.2%) with physician’s choice. Of the 135 patients in the physician’s choice arm, 77 patients had radiographic progression and 70 crossed over to rucaparib. Conclusions: Rucaparib remains the only PARPi to show improved rPFS vs a DTX-containing control arm and has a similar OS even when most patients cross over to rucaparib. Safety was consistent with prior reports. These data support rucaparib as a treatment option for patients with BRCA-mutated mCRPC. Clinical trial information: NCT02975934 . Median OS at final analysis. Group Rucaparib, n Physician's choice, n Rucaparib, months Physician's choice, months HR (95% CI) a BRCA 201 101 23.2 21.2 0.91 (0.68–1.20) ITT 270 135 22.8 21.7 0.99 (0.78–1.26) ATM 69 34 18.4 22.1 1.21 (0.77–1.90) a Calculated by stratified Cox proportional hazard model.

TPS714 Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .

18 Background: TRITON3 (NCT02975934) is a randomized, multicenter, open-label, phase 3 study of rucaparib vs physician’s choice (docetaxel [DTX], abiraterone [ABI] or enzalutamide [ENZ]) in patients (pts) with chemotherapy-naïve mCRPC with BRCA1/2 (BRCA) or ATM alterations. It was previously reported that rucaparib significantly improved the primary endpoint of radiographic progression-free survival (rPFS) vs physician’s choice in pts with BRCA or ATM alterations. We report here the interim overall survival (OS) and also report on efficacy of rucaparib compared individually with either DTX or ABI/ENZ. Methods: Pts had disease progression after 1 prior second-generation androgen pathway inhibitor therapy in any setting and were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI or ENZ. An ordered step-down multiple comparisons procedure was used to control the overall error rate. OS was a key secondary endpoint with rPFS as the primary endpoint tested first in the BRCA subgroup, then the intent-to-treat (ITT) population. Subgroup analyses based on physician’s choice were exploratory. Results: As of August 25, 2022, 302 pts with BRCA and 103 pts with ATM alterations were randomized. OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. rPFS and OS are shown. The most frequent treatment-emergent adverse event (TEAE) in the rucaparib, DTX and ABI/ENZ groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively). The most frequent grade ≥3 TEAE in the rucaparib, DTX and ABI/ENZ groups was anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), respectively. Conclusions: Rucaparib significantly improved rPFS vs either DTX or ABI/ENZ; safety was consistent with prior reports. Interim OS results suggest a trend towards improvement for rucaparib vs DTX or ABI/ENZ in pts with mCRPC and BRCA alterations. Clinical trial information: NCT02975934 . [Table: see text]

TPS586 Background: Chemoradiotherapy(CRT) is a SOC for patients with muscle invasive bladder cancer (MIBC) who refuse or are not fit for radical cystectomy. Radiotherapy and chemotherapy are known to increases the PD-L1 expression in bladder cancer. Based on these observations, we hypothesized that addition of atezolizumab to CRT will increase its efficacy. Methods: This is a randomized phase III trial testing CRT with and without atezolizumab for 6 months in 475 patients with MIBC. Pts will be stratified on performance status (0-1 vs. 2); clinical stage (T2 vs T3/T4a, chemotherapy(cisplatin vs 5FU+mitomycin vs gemcitabine); and radiation field (bladder only vs small pelvis). Patients will undergo biopsy 18 week from registration. If they have residual disease they will be taken off protocol treatment and can proceed with alternative SOC option including radical cystectomy. Patients will be followed for 5 years. The primary end point of the study is bladder intact event –free survival (BIEFS). The event is comprised of: recurrence or residual muscle-invasive bladder cancer at 18 weeks or later, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause. This composite endpoint is reflective of the intent of bladder preservation strategy with radical cystectomy included as one of the outcomes. Secondary end points include overall survival, modified event free survival, pathologic response at 18 weeks, metastasis free survival, cancer specific survival, rate of salvage cystectomy, rate of adverse event and QOL & PRO end points. The expected 3 year BIEFS for the control arm is 52%. The study leadership concluded that a 12% improvement in this endpoint is meaningful for this patient population. With a sample size of 475 patients the study has 85% power to detect the improvement from 52% to 64% in the BIEFS at 3 years (hazard ratio=0.68). The study team will perform translational studies evaluating tumor tissue, whole blood and urine for molecular and immunologic markers of immune response and response to RT. Successful completion of this trial could lead to a new treatment paradigm for patients with muscle invasive bladder cancer. Clinical trial information: NCT03775265.

5029 Background: Pembro had activity as monotherapy in pretreated advanced mCRPC. Data are presented here from cohort B (pembro + docetaxel/prednisone) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC. Methods: Pts who progressed on or became intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and progressed within 6 mo before screening were eligible. Pts received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. The primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age, 68 y; visceral disease, 36%; measurable disease, 50%) began pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths from treatment-related AEs (pneumonitis). Most commonly reported immune-mediated AEs were infusion-related reactions (11%) and colitis (10%). Conclusions: Pembro + docetaxel/prednisone has activity in pts with mCRPC who previously progressed on second-generation hormone therapy. AEs were considered mild for the treatment combination. Clinical trial information: NCT02861573. [Table: see text]