Chen, Ronald C.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

TPS577 Background: Pembrolizumab (pembro) for one year following resection of localized high risk clear cell renal cell carcinoma (ccRCC) in a phase 3 trial resulted in improvement in relapse-free survival and overall survival (Choueiri, NEJM 2024). However, 20% of patients still experienced a relapse within 2 years with no biomarker yet identified to predict who will respond to or needs adjuvant therapy. Addition of a tyrosine kinase inhibitor (TKI) to immunotherapy (IO) is a standard of care in metastatic ccRCC, but to date no studies have addressed the addition of a TKI to IO in the adjuvant setting. Subsequently, phase 3 STRIKE! was developed to explore the benefit of 6 months of tivozanib (tivo) added to pembro vs pembro alone in the adjuvant setting for resected high risk ccRCC. Methods: Eligible patients have an ECOG performance status ≤2 and a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features after complete resection of the primary tumor, with pathology revealing pT2 grade 4 disease or any grade ≥ T3 or TxN1. Patients are also eligible if they developed metastasis within a year after resection and then underwent resection, definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) with no evidence of active disease (M1NED). Patients will be randomized 1:1 to intravenous pembro for 48 weeks with or without the addition of tivo 1.34 mg by mouth daily D1-21 q28D for 6 months stratified by stage (T2T3 vs T4/N1 vs M1NED) . With no limit on dose holds or interruptions of tivo, dose reductions of tivo to 0.89 mg D1-21 q28D or tivo 0.89 mg every other day are allowed. No dose reductions of pembro are permitted. Following baseline imaging to confirm no disease, imaging is performed every 12 weeks for first year, every 16 weeks for second year, every 24 weeks for third year and then annually until 5 years after registration or progression. The primary endpoint will be disease-free survival (DFS) as assessed by investigator, with secondary endpoints being overall survival, safety and tolerability. The study will enroll 1040 patients to detect a minimum detectable hazard ratio of 0.67 (24-month DFS 84% in experimental arm) with 90% power. Quality of life analysis will compare global quality of life and fatigue between the two arms. Imaging and specimens will be banked for future research. The study opened to accrual in April 2025 and at this time 106 patients have enrolled. Clinical trial information: NCT06661720 .

TPS4616 Background: Osseous metastases (OM) occur in approximately 30% patients with advanced RCC. Despite therapeutic advances, OM are associated with poor survival and risk of symptomatic skeletal events (SSEs). Cabozantinib targets multiple tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors and MET (Mesenchymal-Epithelial Transition factor), which are overexpressed in OM, contributing to cabozantinib’s enhanced bone activity. Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in men with metastatic castration-resistant prostate cancer to the bone. Building on this therapeutic approach targeting OM, our pilot study of radium-223 with VEGF inhibition in RCC with OM has also shown safety, improvement in circulating bone turnover markers, and early efficacy (McKay et al, CCR 2018). To address the unmet need to improve SSE rates and outcomes in RCC and OM, we designed a study investigating cabozantinib with or without radium-223 in patients with RCC with OM (NCT04071223). Methods: This is an open-label, multicenter randomized phase-2 study. Key inclusion criteria include metastatic RCC of any histology with ≥1 OM, at least 1 OM without prior radiation, any number of prior therapies, and Karnofsky performance status ≥ 60%. Use of a bone protecting agent is required unless contraindicated. Patients are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223. The starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Radium-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The starting dose for cabozantinib in Arm B is 60 mg daily. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, time to first SSE, objective response rate, time to subsequent anti-cancer therapies, quality of life (QoL) measures, and correlative analyses including liquid biopsy and tumor tissue analysis. The study is designed to have 85% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.05 significance. To ensure 124 evaluable patients, target accrual is 134 (67 per arm). The group-sequential design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events have been observed. The safety run-in, performed in the first 12 patients randomized to combination therapy, did not demonstrate dose limiting toxicities. Final data analysis will occur when 99 events have been observed. The study was activated in July 2020 and accrual is ongoing throughout the National Clinical Trials Network (NCTN). Continued site participation and enrollment are essential to evaluate this therapeutic strategy. Clinical trial information: NCT04071223 .

ABSTRACTBackgroundThis study investigates the association between thromboembolic events (TE) and castration‐resistant prostate cancer (CRPC) patients receiving oral androgen receptor pathway inhibitors (ARPi) compared to those undergoing chemotherapy, both with and without a pre‐existing history of cardiovascular disease (CVD).MethodsA total of 2779 men diagnosed with CRPC were identified using the Surveillance, Epidemiology, and End Results (SEER) Medicare Linked Database from 2012 to 2016. Patients were stratified based on their CVD history. Within each CVD stratum (pre‐existing CVD vs. no pre‐existing CVD), patients were further categorized into two treatment groups: those receiving oral ARPi and those undergoing chemotherapy. Unadjusted and inverse probability treatment weight (IPTW)‐adjusted proportional hazards models, using Fine and Gray's method, were applied to evaluate the potential association between ARPi treatment and TE.ResultsPatients with pre‐existing CVD treated with ARPi exhibited a significantly lower crude hazard ratio (HR) for TE compared to chemotherapy (HR 0.39, 95% CI 0.27–0.58, p < 0.001). However, after adjustment using IPTW, this association was no longer significant (adjusted hazard ratio [AHR] 1.00, 95% CI 0.75–1.32, p = 0.99). For patients without CVD, ARPi use was also associated with a reduced risk of TE in the crude analysis (HR 0.53, 95% CI 0.32–0.87, p = 0.01), but this effect was not statistically significant after IPTW adjustment (HR 0.99, 95% CI 0.69–1.41, p = 0.94).ConclusionARPi demonstrated no significant effect on TE risk compared to chemotherapy, regardless of pre‐existing CVD status. Similarly, when excluding patients with a prior history of TE, ARPi use remained non‐significantly associated with new TE in the IPTW‐adjusted competing risk analysis, highlighting the need for further investigation.

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 .

5006 Background: The PRESTO trial (NCT03009981) showed that in patients with biochemically relapsed prostate cancer following radical prostatectomy with a PSA doubling time of ≤ 9 months and without evidence of metastatic disease by conventional imaging, intensified androgen receptor blockade for 52 weeks (androgen deprivation therapy [ADT] plus apalutamide [Apa], or ADT plus Apa and abiraterone acetate [Abi] plus prednisone) prolonged PSA progression-free survival compared to ADT alone (Aggarwal et al, JCO 2024). Here we report the HRQOL results. Methods: HRQOL measures included the Hot Flash Related Daily Interference Scale (HFRDIS), Expanded Prostate Cancer Index Composite (EPIC)-26 Sexual domain, PROMIS Fatigue Short Form and EQ-5D-5L, which assesses overall HRQOL in the 504 randomized patients. Published minimally important difference thresholds for these HRQOL measures are: HFRDIS 1.66 points, EPIC Sexual 10-12, PROMIS Fatigue 3-5, and EQ-5D-5L 0.06. General linear mixed modeling was used to estimate between-arm mean differences in HRQOL according to an intent-to-treat approach. Results: Mean changes from baseline to end of treatment (EOT) for each arm and for each HRQOL measure are summarized in Table. No statistically significant mean difference was reported between intensified androgen receptor blockade (Arm B, Arm C) vs ADT alone (Arm A) in any HRQOL measure. Further, numerical differences across arms for all HRQOL measures are below published minimally clinically important difference thresholds. Conclusions: Intensified androgen receptor blockade with Apa or Apa/Abi added to 52 weeks of ADT improves PSA progression-free survival without negatively affecting HRQOL. These HRQOL results add further support to intensification of androgen blockade in patients with high-risk biochemically recurrent prostate cancer. Clinical trial information: NCT03009981 . [Table: see text]

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 .