kiyoshi takahara

BACKGROUND: Upfront treatment intensification with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor has become a standard approach for metastatic hormone-sensitive prostate cancer (mHSPC). However, prognosis remains poor for some patients despite second-generation androgen receptor antagonist-based doublet therapy. Although triplet therapy with darolutamide and docetaxel is available, its added clinical value over apalutamide- or enzalutamide-based doublet therapy in real-world practice remains unclear. Gleason pattern 5 (GP5) reflects aggressive tumor biology and may be relevant for treatment selection. We evaluated whether triplet therapy was associated with longer castration-resistant prostate cancer-free survival (CRPC-FS) than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC, with a particular focus on effect modification by GP5 status. METHODS: This retrospective multicenter cohort study used the ULTRA-J multicenter collaborative database in Japan. We included systemic treatment-naïve patients with mHSPC who received either doublet therapy with ADT plus apalutamide or enzalutamide, or triplet therapy with ADT, darolutamide, and docetaxel, between February 2018 and October 2024. The final analytic cohort consisted of 294 patients. Overlap weighting was used to reduce treatment-selection bias. The primary endpoint was CRPC-FS, and overall survival (OS) was assessed as a supportive endpoint. Progression-free survival 2 (PFS2) and post-CRPC docetaxel use were evaluated as exploratory post-progression outcomes. RESULTS: The median follow-up duration estimated using the reverse Kaplan-Meier method was 18.0 months in the doublet group and 11.0 months in the triplet group. In the overlap weighting-adjusted overall cohort, triplet therapy was associated with longer CRPC-FS than doublet therapy (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.13-0.64; p = 0.002). A significant interaction was observed for GP5 status (p for interaction = 0.037). In the GP5-positive subgroup, triplet therapy was associated with longer CRPC-FS than doublet therapy (HR, 0.16; 95% CI, 0.06-0.42; p < 0.001), whereas no clear advantage of triplet therapy was observed in the GP5-negative subgroup (HR, 1.85; 95% CI, 0.29-11.94; p = 0.52). No clear difference in OS was observed at the current follow-up. CONCLUSIONS: Triplet therapy was associated with longer CRPC-FS than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC. This association appeared more evident in patients with GP5-positive disease. Given the shorter follow-up in the triplet group, limited event numbers in subgroup and PFS2 analyses, and the nonrandomized nature of post-CRPC treatment sequencing, these findings should be interpreted as hypothesis-generating.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based combination therapies, including immune checkpoint inhibitor plus immune checkpoint inhibitor (IO + IO) and immune checkpoint inhibitor plus tyrosine kinase inhibitor (IO + TKI) regimens, have significantly improved outcomes in metastatic renal cell carcinoma (mRCC). However, the prognostic impact of host-related factors in patients receiving these therapies remains unclear. METHODS: We retrospectively analyzed 493 patients with mRCC treated with IO+IO (n = 205) or IO+TKI (n = 288) as first-line therapy. Survival outcomes and treatment responses were evaluated according to host-related factors using Cox proportional hazards models. RESULTS: In the IO+IO cohort, multiple host-related factors were independently associated with worse overall survival, including BMI < 25 kg/m2 (HR 2.280, p = 0.007), dyslipidemia (HR 2.079, p = 0.019), PPI use (HR 1.605, p = 0.039), and opioid use (HR 2.919, p = 0.008). In contrast, in the IO+TKI cohort, only IMDC poor risk (HR 4.169, p < 0.001) and opioid use (HR 3.328, p < 0.001) were significantly associated with overall survival. Host-related factors showed limited associations with objective response and disease control rates in both cohorts. CONCLUSION: The prognostic impact of host-related factors differs according to treatment regimen in mRCC. These findings suggest that host immune and metabolic conditions play a more prominent role in immune-driven IO+IO therapy, whereas tumor-related factors may predominate in IO+TKI therapy.

BACKGROUND: Enfortumab vedotin plus pembrolizumab (EV/Pem) has improved the survival of patients with advanced urothelial carcinoma; however, many patients suffer treatment-related adverse events, particularly skin toxicity. This study aimed to clarify the clinical impact of skin-toxicity timing on treatment outcomes. METHODS: We retrospectively analyzed patients with advanced urothelial carcinoma treated with EV/Pem. Patients were categorized into three groups according to skin-toxicity timing: no rash, early-onset rash (< 1 month), and late-onset rash (≥ 1 month). Baseline clinical and laboratory characteristics were compared among groups and incorporated into multivariable Cox proportional hazards analyses. Kaplan-Meier analyses with pairwise log-rank tests were performed to evaluate progression-free survival (PFS) and overall survival (OS). The 1-month cutoff was selected for clinical interpretability. RESULTS: The three-group analysis included 210 patients: no rash (n = 87), early-onset rash (n = 84), and late-onset rash (n = 39). Late-onset rash was associated with significantly prolonged PFS and OS in conventional analyses. In multivariable analysis, late-onset rash was significantly associated with prolonged PFS (HR 0.34, 95% CI 0.15-0.74, p = 0.007) and OS (HR 0.25, 95% CI 0.07-0.81, p = 0.02). Because late-onset rash could only be assigned after continued observation, these associations should be interpreted as exploratory and potentially affected by immortal time bias. In the 3-month landmark analysis, PFS remained significantly longer in the late-onset than early-onset rash group, whereas OS did not differ significantly. CONCLUSIONS: Skin toxicity during EV/Pem therapy appears to have timing-dependent prognostic implications. Late-onset rash showed favorable outcomes in conventional analyses, but these findings should be considered hypothesis-generating.

BACKGROUND: Enfortumab vedotin plus pembrolizumab (EVP) has emerged as a standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). However, large-scale real-world data in Japanese patients remain limited. METHODS: We retrospectively analyzed consecutive patients with la/mUC who received first-line EVP across multiple Japanese centers. Oncologic outcomes including tumor response, progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), and adverse events (AEs) were assessed. Survival was estimated using the Kaplan-Meier method, and exploratory analyses were performed to identify factors associated with OS, PFS and objective response rate (ORR). RESULTS: A total of 212 patients were included. The median age was 75 years, and 23 patients (10.8%) had ECOG performance status (PS) ≥2. Among 201 evaluable patients, ORR was 63% including 12.5% of complete response. Subgroup analysis of ORRs showed broadly consistent efficacy across diverse patient or cancer characteristics. The median PFS, CSS, and OS was 12.0, 15.0, and 12.9 months, respectively. Liver metastasis was associated with poor PFS (HR 2.35, P = 0.012), ECOG PS ≥ 2 was associated with poor OS (HR 2.84, P = 0.002), and variant histology was associated with poorer PFS (HR 3.19, P < 0.001) and OS (HR 2.6, P = 0.001). Any-grade AEs occurred in 87% of patients, and severe AEs occurred in 34%. Skin-related AEs were the most frequent toxicity, occurring in 59% of patients, with grade ≥3 skin-related AEs in 11%. Median time to onset of skin-related AEs was 15.5 days. CONCLUSIONS: In this multicenter Japanese real-world cohort, first-line EVP demonstrated favorable antitumor activity with manageable but frequent toxicities, particularly early skin AEs. These findings support the effectiveness of EVP in routine practice while underscoring the importance of proactive AE management and careful risk stratification, including histologic subtype.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based combination therapy (ICI plus ICI [IO-IO] or ICI plus tyrosine kinase inhibitor [IO-TKI]) is the standard first-line treatment for metastatic renal cell carcinoma (mRCC), but its impact in patients undergoing maintenance hemodialysis (HD) relative to non-HD patients remains unclear. METHODS: We retrospectively compared patients with mRCC who received first-line IO-IO or IO-TKI therapy (2018-2025) according to HD status at treatment initiation. Oncologic outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) and safety were assessed in the crude cohort and after inverse probability of treatment weighting (IPTW) based on propensity scores. IO-IO and IO-TKI regimens were also compared within the HD cohort. RESULTS: Among 601 patients, 37 were receiving HD. In the crude cohort, HD patients had significantly worse PFS, OS, and ORR (37% vs. 57%) than non-HD patients. After IPTW, PFS remained significantly shorter in the HD group (hazard ratios [HR] 1.76, 95% confidence interval [CI] 1.21-2.57; P = 0.003), whereas OS (HR 1.49, 95% CI 0.89-2.50; P = 0.1) and ORR (odds ratios 0.58, 95% CI 0.22-1.54; P = 0.3) were no longer significant. Safety, including Grade ≥3 adverse events, was comparable. Among HD patients, PFS and OS did not differ between IO-IO and IO-TKI regimens. CONCLUSIONS: In mRCC patients undergoing HD, first-line ICI-based combination therapy was associated with significantly shorter PFS, whereas the worse crude OS and ORR were attenuated after adjustment, largely reflecting baseline prognostic differences rather than reduced efficacy. With a comparable safety profile, it may be a reasonable option in selected patients undergoing HD.