Jacene, Heather A

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.

PURPOSE 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes—both pathologic and time-to-event survival end points—particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor–positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.