Gontero, Paolo

Objectives To evaluate biochemical recurrence‐free survival (BRFS) and metastasis‐free survival (MFS) as potential intermediate clinical endpoints (ICEs) for overall survival (OS) in patients undergoing salvage radical prostatectomy (sRP). Patients and Methods Evaluable patients were selected from a retrospective dataset, resulting in a cohort of 879 patients with recurrent, non‐metastatic, hormone‐sensitive prostate cancer treated with sRP at 13 centres. ICE surrogacy was evaluated using a two‐stage approach: (i) at the individual‐patient level by fitting Clayton copula models and estimating Kendall's ( >0.7 indicating a strong association) and (ii) at the centre level, by fitting weighted linear regression of 5‐year OS on 3‐year BRFS and MFS. Results The two‐step analysis included 759 patients for BRFS (366 events) and 476 for MFS (137 events), with median follow‐up of 37 months (95% confidence interval [CI] 36–42 months) and 34 months (95% CI 31–37 months), respectively. At the individual‐patient level, MFS showed a strong association with OS (Kendall's 0.85, 95% CI 0.82–0.88), which was not observed for BRFS (Kendall's 0.63, 95% CI 0.56–0.69). At the centre level, neither 3‐year BRFS ( R 2 = 0.15; slope = 0.34, P = 0.2) nor 3‐year MFS ( R 2 = 0.21; slope = 0.26, P = 0.14) predicted 5‐year OS with sufficient explanatory power. Limitations include the fact that centre‐level analysis was based on single‐arm associations rather than on treatment‐effect surrogacy across arms, and retrospective data collection. Conclusions The BRFS should not be used as a surrogate endpoint in the sRP setting. MFS requires further validation in future prospective studies to confirm its association with OS. Patient‐reported outcomes, such as quality‐of‐life and treatment‐related toxicity, should be considered in parallel with OS.

Objective To validate International Bladder Cancer Group (IBCG) definitions of Bacillus Calmette‐Guérin (BCG)‐unresponsive and BCG‐exposed non‐muscle‐invasive bladder cancer (NMIBC) and assess prognostic heterogeneity across various BCG‐failure types. Patients and Methods From a multicentre international cohort of 3806 BCG‐treated patients, 591 who developed high‐grade NMIBC recurrence following BCG between 2003 and 2024 were included. Progression‐free survival (PFS) was the primary endpoint; cancer‐specific (CSM) and overall mortality (OM) were secondary endpoints. Cumulative incidence functions, competing‐risk models and multivariable Cox regression were used. Results Patients with BCG‐unresponsive and BCG‐exposed disease showed similar PFS, CSM, and OM (all P > 0.05). When stratified into five subgroups, prognosis varied: 5‐year progression rates were 29% for BCG‐unresponsive, 32.5% for late relapse (between 6 and 24 months) after adequate BCG, 30% for BCG‐exposed with inadequate BCG (<24 months from induction), 6.2% for BCG‐resistant, and 14% for very late relapse (>24 months since last BCG) ( P < 0.01). In multivariable analysis, BCG‐exposed after inadequate BCG (subdistribution hazard ratio [sHR] 3.42, 95% confidence interval [CI] 1.33–8.84), late relapse (sHR 3.74, 95% CI 1.59–8.78), and BCG‐unresponsive (sHR 2.34, 95% CI 1.00–5.44) were associated with higher progression risks compared to very late relapse. Limitations include retrospective design and treatment heterogeneity. Conclusions Under IBCG definitions, BCG‐unresponsive and BCG‐exposed NMIBC have similarly poor outcomes. A refined classification reveals prognostic heterogeneity, with late relapses after adequate BCG demonstrating outcomes comparable to BCG‐unresponsive, and very late relapses conferring better prognosis.

TPS4630 Background: Bacillus Calmette-Guérin (BCG) is the standard first-line therapy for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors; however, patients whose disease is unresponsive to BCG therapy are unlikely to benefit from further courses of BCG. Bladder-preserving treatment options for patients with BCG-unresponsive NMIBC with CIS ± Ta/T1 include intravesical gene therapy (nadofaragene firadenovec-vncg), intravesical chemotherapy (gemcitabine and docetaxel), and immunotherapy (intravenous pembrolizumab and intravesical nogapendekin alfa inbakicept-pmln). In a pivotal phase 3 study, 53.4% of participants (55/103) with BCG-unresponsive NMIBC with CIS ± Ta/T1 achieved a complete response (CR) within 3 months of a single instillation of nadofaragene firadenovec, and of them, 45.5% (25/55) maintained a CR at 12 months. Nadofaragene firadenovec in combination with chemotherapy or immunotherapy may further improve clinical efficacy. ABLE-22 (NCT06545955) is an interventional study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in participants with high-risk BCG-unresponsive NMIBC. Participants not responding at month 3 will be offered reinduction. Methods: ABLE-22 will include approximately 40 to 75 sites across the United States and Canada; sites in Asia, Australia, and Europe may be included. Participants (anticipated N = 150) will be randomly assigned 1:1:1 to receive nadofaragene firadenovec (n = 50), nadofaragene firadenovec plus gemcitabine and docetaxel (n = 50), or nadofaragene firadenovec plus pembrolizumab (n = 50). Adults aged ≥18 years with documented NMIBC with CIS ± Ta/T1 that is unresponsive to ≥2 courses of BCG therapy within the last 12 months are eligible to enroll. The primary endpoint is CR (defined as absence of low- and high-grade NMIBC) at months 3 or 6, as participants with persistent NMIBC (any CIS, low-grade Ta, and > 3 cm or multifocal high-grade Ta) will be offered reinduction once, at month 3. Secondary endpoints include durability of CR, incidence of muscle-invasive progression, cystectomy-free survival, pathologic staging, overall survival, and safety. Durability of CR will be followed up to month 36 (assessed quarterly for the first 24 months); all other secondary endpoints will be assessed up to and including month 36. Exploratory endpoints include changes in expression of potential biomarkers in blood and urine. Results from this investigational, randomized, multicenter, open-label study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy are expected July 2028. Clinical trial information: NCT06545955 .

TPS891 Background: Bacillus Calmette-Guérin (BCG) is the standard first-line therapy for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors; however, patients whose disease is unresponsive to BCG therapy are unlikely to benefit from further courses of BCG. Bladder-preserving treatment options for patients with BCG-unresponsive NMIBC with CIS ± Ta/T1 include intravesical gene therapy (nadofaragene firadenovec-vncg), intravesical chemotherapy (gemcitabine and docetaxel), and immunotherapy (intravenous pembrolizumab and intravesical nogapendekin alfa inbakicept-pmln). In a pivotal phase 3 study, 53.4% of participants (55/103) with BCG-unresponsive NMIBC with CIS ± Ta/T1 achieved a complete response (CR) within 3 months of a single instillation of nadofaragene firadenovec, and of them, 45.5% (25/55) maintained a CR at 12 months. Nadofaragene firadenovec in combination with chemotherapy or immunotherapy may further improve clinical efficacy. ABLE-22 (NCT06545955) is an interventional study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in participants with high-risk BCG-unresponsive NMIBC. Reinduction for nonresponders once at month 3 will also be evaluated. Methods: ABLE-22 will include approximately 40 to 75 sites across the United States and Canada; however, sites in Asia, Australia, and Europe may be included. Participants (anticipated N=150) will be randomly assigned 1:1:1 to receive nadofaragene firadenovec (n=50), nadofaragene firadenovec plus gemcitabine and docetaxel (n=50), or nadofaragene firadenovec plus pembrolizumab (n=50). Adults aged ≥18 years with documented NMIBC with CIS ± Ta/T1 that is unresponsive to ≥2 courses of BCG therapy within the last 12 months are eligible to enroll. The primary endpoint is CR (defined as absence of low- and high-grade NMIBC) at months 3 or 6, as participants with persistent NMIBC (any CIS, low-grade Ta, and >3 cm or multifocal high-grade Ta) will be offered reinduction once, at month 3. Secondary endpoints include durability of CR, incidence of muscle-invasive progression, cystectomy-free survival, pathologic staging, overall survival, and safety. Durability of CR will be assessed quarterly up to and including month 24; all other secondary endpoints will be assessed up to and including month 36. Exploratory endpoints include changes in expression of potential biomarkers in blood and urine. Results from this investigational, randomized, multicenter, open-label study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy are expected July 2028. Clinical trial information: NCT06545955 .

Background: Lymph node invasion (LNI) represents a poor prognostic factor after primary radical prostatectomy (RP) for prostate cancer (PCa). However, the impact of LNI on oncologic outcomes in salvage radical prostatectomy (SRP) patients is unknown. Objective: To investigate the impact of lymph node dissection (LND) and pathological lymph node status (pNX vs. pN0 vs. pN1) on long-term oncologic outcomes of SRP patients. Patients and methods: Patients who underwent SRP for recurrent PCa between 2000 and 2021 were identified from 12 high-volume centers. Kaplan–Meier analyses and multivariable Cox regression models were used. Endpoints were biochemical recurrence (BCR), overall survival (OS), and cancer-specific survival (CSS). Results: Of 853 SRP patients, 87% (n = 727) underwent LND, and 21% (n = 151) harbored LNI. The median follow-up was 27 months. The mean number of removed lymph nodes was 13 in the LND cohort. At 72 months after SRP, BCR-free survival was 54% vs. 47% vs. 7.2% for patients with pNX vs. pN0 vs. pN1 (p < 0.001), respectively. At 120 months after SRP, OS rates were 89% vs. 81% vs. 41% (p < 0.001), and CSS rates were 94% vs. 96% vs. 82% (p = 0.02) for patients with pNX vs. pN0 vs. pN1, respectively. In multivariable Cox regression analyses, pN1 status was independently associated with BCR (HR: 1.77, p < 0.001) and death (HR: 2.89, p < 0.001). Conclusions: In SRP patients, LNI represents an independent poor prognostic factor. However, the oncologic benefit of LND in SRP remains debatable. These findings underline the need for a cautious LND indication in SRP patients as well as strict postoperative monitoring of SRP patients with LNI.

Introduction: Salvage lymph node dissection (sLND) is a treatment option for prostate cancer (PCa) patients with nodal recurrence after radical therapy to delay tumour progression and hormonal treatment. We evaluated the outcomes in terms of biochemical recurrence (BCR), clinical regression, and cancer specific survival (CSS) in a large, multicentric series of patients treated with sLND for nodal recurrence of PCa. Methods: We retrospectively reviewed the records of 106 consecutive patients with BCR of PCa after radical treatment who underwent sLND between 2007 and 2013 at three tertiary centres. BCR was defined as prostate-specific antigen (PSA) >0.2 ng/mL. Clinical recurrence (CR) was defined as a positive imaging study or biopsy for metastasis after sLND. Kaplan–Meier curves calculated BCR-free survival (BFS), CR-free survival (CRS), and CSS. Cox regression analyses were performed to identify predictors of CR. Results: Median number of nodes removed at sLND was 21.7, with a median of three positive nodes. Immediate biochemical response after surgery was achieved in 50.9% of patients. At a median follow-up of 22.5 months, biochemical failure and CR were experienced by 67.9% and 40.5% of patients, respectively. At 2 years, BFS, CRS, and CSS were 25%, 52%, and 92%, respectively. Castrate-resistant prostate cancer (CRPC) status, PSA level at sLND, and presence of biochemical failure after sLND were significantly associated with CR after surgery. Conclusions: sLND represents a valid treatment option for selected patients with nodal recurrences, achieving a CR-free status in more than half of patients at 2 years. Patients with CRPC status or high PSA values might not be the best candidates for a sLND.

AbstractBackgroundA recent meta‐analysis (Human Reproduction Update 23, 2017 and 265) reported positive sperm retrieval rates (SRR) in 50% of patients with Klinefelter syndrome (KS) undergoing testicular sperm extraction (TESE). However, these results do not reflect the rates of SR that we observe in clinical practice. We assessed the rate and potential predictors of SR in Klinefelter patients in the real‐life setting.Materials and MethodsWe reviewed clinical data of 103 KS men who underwent TESE between 08/2008 and 03/2019 at five tertiary referral Andrology centers. Patients underwent testis ultrasound, hormonal evaluation, and genetic testing. All patients were azoospermic based on the 2010 WHO reference criteria. Conventional TESE (cTESE) or microsurgical TESE (mTESE) was performed based on the surgeon's preference. We used descriptive statistics and logistic regression models to describe the whole cohort.ResultsMedian (IQR) patient's age was 32 (24‐37) years. Baseline serum FSH and total testosterone levels were 29.5 (19.9‐40.9) mUI/mL and 3.8 (2.5‐11.0) ng/mL, respectively. Conventional TESE and mTESE were performed in 38 (36.5%) and 65 (63.5%) men, respectively. The sperm retrieval rate was 21.4% (22/103 men). Fifteen patients used spermatozoa for ICSI and five ended in live birth children. Patients with positive SR were similar to those with a negative TESE in terms of clinical, hormonal, and procedural parameters (all P > .05). Logistic regression analyses confirmed the lack of association between clinical, hormonal, and procedural parameters with SR outcome.DiscussionGiven the conflicting results in the literature regarding SRR in KS, patients should be carefully counseled regarding TESE outcomes based on data from published literature and local results.ConclusionsIn the real‐life setting, we observed a lower SRR (21.4%) than that reported in meta‐analyses in our cohort of KS patients. No associations between clinical, hormonal, and procedural variables with TESE success were found.

140 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach but patients with positive section margins (R1) disease have not always the same cancer-specific survival (CSS). The current study aims to analyze current postoperative pathological features in order to predict CSS of HRPC patients with R1, but with negative lymph nodes (pN0), treated with surgery. Methods: From a multi-institutional retrospective cohort of 5,876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1541 patients with pN0 and R1 were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and p-Gleason score (pGS≥8 and pGS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age at surgery was 66 years (42-89). Of all patients, 399 (25.9%) had GS≥8 and 999 (64.8%) had pT≥3 at definitive histopathology. Patients were classified as COMBO groups: C1 (423; 27.4%; GS<8,pT<3), C2 (674; 43.7%; GS<8, pT≥3), C3 (83; 5.4%; GS≥8, pT<3), C4 (362; 23.5%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 3%/5%, C2 15%/21%, C3 21%/20%, C4 28%/40%. Kaplan-Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97%, C2 93.8%, C3 85.1% and C4 77.3% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide margin-positive, pN0 HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]