髙原 健

BACKGROUND/AIM: Oncological outcomes for metastatic castration-sensitive prostate cancer (mCSPC) have improved with upfront androgen receptor signaling inhibitor (ARSI) doublet therapy. However, the prognostic value of prostate-specific antigen (PSA) kinetics in real-world settings remains unclear. This study aimed to evaluate the clinical significance of PSA kinetics in patients with high-risk mCSPC. PATIENTS AND METHODS: We retrospectively analyzed 352 patients with high-risk mCSPC from the ULTRA-J database who received upfront ARSI doublet therapy between 2018 and 2023. PSA kinetics, including PSA nadir, PSA response rate, and time to PSA nadir (TTN), were assessed. Associations with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: A PSA nadir ≤0.02 ng/ml and PSA response rate ≥99% were significantly associated with prolonged CRPC-FS and OS (p<0.05). Conversely, TTN ≤3 months was associated with poorer outcomes. Multivariate analysis identified PSA nadir >0.02 ng/ml, PSA response rate <99%, and TTN ≤3 months as independent predictors of shorter CRPC-FS and OS. These trends were generally consistent across ARSI agents, although some differences were observed in subgroup analyses. CONCLUSION: PSA kinetics are strong independent prognostic factors in patients with high-risk mCSPC treated with upfront ARSI doublet therapy. These readily available biomarkers may help identify patients who require treatment intensification or closer monitoring in clinical practice.

BACKGROUND/AIM: Existing prognostic models for metastatic renal cell carcinoma (mRCC) were developed using all-age cohorts, and their validity in non-elderly patients remains unclear. We aimed to develop and validate our prognostic model for patients aged ≤65 years with mRCC, including non-clear cell histologies, and to establish a practical risk stratification system. PATIENTS AND METHODS: We retrospectively analyzed 210 patients with mRCC from multiple Japanese institutions. The primary endpoint was overall survival (OS). Independent prognostic factors were identified using a multivariable Cox regression analysis. A simplified scoring system was constructed to stratify patients into risk groups. Model discrimination was evaluated using the concordance index (C-index), with internal validation by bootstrap resampling. Clinical utility was assessed by a decision curve analysis (DCA). A nomogram was constructed based on the identified independent prognostic factors. RESULTS: During a median follow-up of 57 months, 77 OS events occurred; median OS was 65.7 months. Histopathological type, liver metastasis, C-reactive protein, serum-corrected calcium, and time to systemic therapy were independently associated with worse OS. Our prognostic model stratified patients into favorable- (n=89), intermediate- (n=76), and poor- (n=45) risk groups, with median OS of 95.1, 37.7, and 9.6 months, respectively (p<0.001). The 5-year C-index was 0.74, exceeding that of the International Metastatic RCC Database Consortium (IMDC) model (0.70). In DCA, our prognostic model showed higher net benefit across threshold of 0.3-0.6, corresponding to an average reduction of 3.26 unnecessary treatment escalations per 100 patients. The nomogram showed time-dependent C-indices of 0.83, 0.84, and 0.87 at 1, 3, and 5 years. CONCLUSION: Our prognostic model provides superior discrimination to and higher clinical utility than the IMDC model for predicting OS in non-elderly patients with mRCC, supporting age-specific risk stratification in this population.

OBJECTIVES: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive histological variant associated with a poor prognosis. While immune checkpoint inhibitor (ICI)-based combinations have become the standard of care, the optimal first-line regimen, specifically dual immunotherapy (IO-IO) vs. IO plus tyrosine kinase inhibitor (IO-TKI), remains controversial. We herein examined the real-world clinical outcomes of Japanese patients with sRCC. METHODS: We conducted a retrospective multicenter study on 46 patients with advanced or metastatic sRCC receiving first-line ICI-based combination therapy between January 2018 and December 2024 (IO-IO: n = 18; IO-TKI: n = 28). In a comparative survival analysis, three favorable-risk patients in the IO-TKI group were excluded to align risk profiles, focusing on intermediate/poor-risk groups (n = 43). The primary endpoint was overall survival (OS). RESULTS: In the entire cohort (n = 46), the objective response rate was numerically higher in the IO-TKI group (64.3%) than in the IO-IO group (50.0%) (p = 0.37). In the comparative analysis of intermediate/poor-risk patients (n = 43), progression-free survival (PFS) was slightly longer (p = 0.071), and OS was significantly longer (p = 0.016) in the IO-TKI group than in the IO-IO group. A multivariable analysis adjusted for IMDC risk categories showed favorable survival with the IO-TKI regimen (HR 0.37, p = 0.061). CONCLUSIONS: The present study indicates that first-line IO-TKI combination therapy represents a promising treatment option with a potential survival advantage over IO-IO therapy for Japanese patients with sRCC. However, due to the retrospective design and small sample size, reliably determining the comparative efficacy of these regimens remains challenging, and further validation is warranted.

BACKGROUND: Standard first-line treatment for patients with advanced renal cell carcinoma (aRCC) has commonly included combined immune-oncology (IO) agents (IO-IO) or combinations of a tyrosine kinase inhibitor (TKI) and an IO agent (IO-TKI); however, there are few head-to-head comparative real-world studies, especially involving Japanese cohorts. OBJECTIVE: To compare prognoses of patients treated with IO-IO or IO-TKI therapy in routine Japanese clinical practice. METHODS: This retrospective study included 416 International Metastatic RCC Database Consortium (IMDC) intermediate- and poor-risk patients with aRCC treated with either IO-IO or IO-TKI at four institutions from September 2018 to February 2026. Effectiveness and safety outcomes were comprehensively compared. Overall (OS) and progression-free survival (PFS) rates were estimated with the Kaplan-Meier method. RESULTS: We used propensity-score matching to compare 324 patients (IO-IO: 162; IO-TKI: 162). The IO-TKI cohort showed significantly higher objective response rates than the IO-IO cohort (66 versus 44%, respectively, p < 0.01), longer PFS (17.1 versus 8.4 months, respectively, HR = 0.56, p < 0.01), and longer OS (51.7 versus 31.5 months, respectively, HR = 0.70, p = 0.04), although OS did not reach significance in the IMDC risk-stratified subgroups. While all-grade adverse events (AEs) were more common in the IO-TKI group (94 versus 83%, respectively, p < 0.01), rates of immune-related AEs and corticosteroid administration were significantly higher in the IO-IO cohort. The study limitations include the retrospective design and treatment strategy solely decided by each physician. CONCLUSIONS: IO-TKI combinations were associated with higher rates of adverse events but survival benefits in IMDC intermediate- and poor-risk patients with aRCC.

Few studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO-IO and IO-tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoint was objective response rate. Efficacy was compared between IO-IO and IO-TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO-IO and IO-TKI. In bone metastases (n = 80), OS tended to favor IO-TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO-TKI (P = 0.011). IO-TKI may be a more appropriate first-line option than IO-IO for mRCC with bone or liver metastases, while efficacy is similar for other sites.