TPS5147 Background: Androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPIs) is the standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). However, a substantial proportion of patients fail to achieve a deep prostate-specific antigen (PSA) response, which is consistently associated with worse outcomes. Deep PSA response has emerged as a robust early prognostic marker across multiple phase III trials. Patients lacking this favorable PSA decline represent a poor-risk subgroup with limited treatment personalization. Docetaxel improves survival in high-volume mHSPC and may benefit biologically aggressive disease identified by suboptimal early PSA response. REINFORCE evaluates a PSA-guided strategy of treatment intensification with docetaxel in patients without deep PSA response after apalutamide. Methods: REINFORCE is an international, multicenter, open-label, phase III randomized trial. Eligible patients are men ≥18 years with histologically confirmed mHSPC, ECOG performance status ≤1, PSA > 5 ng/ml at diagnosis of metastatic disease, ≤12 weeks of ADT before apalutamide, adequate organ function, who have received apalutamide plus ADT for 24–30 weeks, have not progressed, and have failed to achieve a deep PSA response. Deep PSA response is defined as PSA ≤ 0.2 ng/ml or PSA response ≥ 90% in combination with a PSA ≤4 ng/ml. Approximately 320 patients from 85 sites located in 6 countries will be randomized 1:1 to treatment intensification with docetaxel (75 mg/m² every 3 weeks for 6 cycles) plus continued apalutamide and ADT, or continuation of apalutamide plus ADT alone. Randomization is stratified by metastasis timing (synchronous vs metachronous), presence of visceral metastases, and PSA at study entry (≤4 vs > 4 ng/mL). The primary endpoint is event-free survival (EFS), defined as time from randomization to PSA progression, radiographic progression of soft tissue, visceral or bone lesions, according to PCWG3, or death from any cause. Secondary endpoints include time to castration resistance, radiographic and PSA progression-free survival, overall survival, safety, PSA response rates, and patient-reported outcomes. Preliminary evidence suggests that apalutamide is associated with a ≲ 10% decrease in docetaxel AUC; a dedicated pharmacokinetic sub-study will assess docetaxel drug-drug interaction and bioequivalence when co-administered with apalutamide. An independent data monitoring committee will oversee patient safety, including an early safety review after the first 18 patients included, review a pre-planned interim efficacy analysis, and evaluate pharmacokinetic data, providing recommendations to the sponsor regarding study continuation. Clinical trial information: 2025-524408-30-00.

Therapeutic drug monitoring of protein kinase inhibitors (PKIs) usually relies on the measure of a single trough concentration at steady-state (Cmin,ss). When the sampling time differs from the trough, it is theoretically possible to predict Cmin,ss from maximum a posteriori (MAP) Bayesian estimates of PK parameters. However, several questions remain with regards to model-informed precision dosing (MIPD) of PKIs, such as choosing which model to use when several are available in the literature. Alternative techniques, such as flattened priors and model averaging may outperform standard analyses. The aim of this work is to report a comprehensive fit-for-purpose validation of MIPD for sunitinib and pazopanib. Concentration data from 41 renal cancer patients included in the SUP-R trial (NCT02555748) measured 2 and 6 hours after an intake were analyzed (MAP-Bayesian estimation of PK parameters) in order to predict Cmin,ss at the current cycle and at the next cycle. Different models from the literature were tested, as well as the model-averaging and flattened priors features available in the R package ‘mapbayr’. The quality of Cmin,ss predictions depended on the model used. Flattening priors rarely improved or worsened the predictions. Model averaging was robust across the different scenarios tested and should be preferred to using a single model. Overall, a precision of 20

Metastatic castration-resistant prostate cancer (mCRPC) remains challenging to treat, especially after failure of standard therapies, such as androgen receptor pathway inhibitors and taxane-based chemotherapy. Radiopharmaceutical therapy with [177Lu]Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA)-positive tumor cells. In the VISION trial, [177Lu]Lu-PSMA-617 has demonstrated significant benefits in terms of median overall survival and a significant improvement of median radiographic progression-free survival (PFS) versus standard of care. Recent guidelines support its use in PSMA-positive mCRPC. In France, [177Lu]Lu-PSMA-617 was available via an early-access program from December 1, 2021, to April 29, 2025. This analysis reports the largest real-world cohort of patients with mCRPC treated with [177Lu]Lu-PSMA-617, evaluating its use, safety, and effectiveness in routine clinical practice. Methods: This multicenter descriptive cohort included adult patients with mCRPC who had progressive disease after at least 1 androgen receptor pathway inhibitor and 1 taxane-based treatment, and 1 positive PSMA PET scan. Patients received up to 6 cycles of intravenous [177Lu]Lu-PSMA-617 every 6 wk. Clinical evaluation, prostate-specific antigen (PSA) status, imaging assessments, and treatment-related adverse events were prospectively collected during regular follow-up. PFS was analyzed using Kaplan-Meier methods. Outcomes were compared descriptively to the VISION trial. Results: From December 2021 to April 2025, 3709 patients from 46 centers received at least 1 dose and 2476 had more than 8 mo of follow-up for efficacy analysis. Compared with VISION, patients were older, more heavily pretreated, and had more lymph node metastases but lower baseline PSA. Median imaging PFS was 7.6 mo versus 8.7 mo in VISION. Disease control was achieved in 82% according to PSA criteria. Some patients with early PSA progression after the first cycle subsequently showed a response, suggesting a flare-up effect. The safety profile was manageable, with treatment discontinuations mainly due to progression. No new safety signals were identified. Subgroup analyses confirmed efficacy in elderly patients (aged >75 y) and more favorable outcomes in patients less heavily pretreated with taxane-based chemotherapy. Conclusion: The French early-access program confirms a favorable benefit-risk profile for [177Lu]Lu-PSMA-617 in a real-world mCRPC population. Use trends suggest earlier use of the treatment after 1 taxane-based treatment, with patients being less pretreated and characterized by fewer metastases.

The prostate cancer (PCa) treatment landscape, particularly metastatic PCa, is rapidly evolving, with an increase in personalised treatment approaches and therapy selection being guided by tumour genomics. However, PCa remains the third leading cause of death among male-specific cancers in the European Union. Nearly a quarter of patients with metastatic PCa harbour homologous recombination repair (HRR) pathway mutations, with approximately 12% harbouring alterations in the BRCA1 or BRCA2 genes. These genomic alterations are associated with poorer prognosis and increased sensitivity to targeted therapies, such as poly(adenosine diphosphate-ribose) polymerase inhibitors. There is an urgent need to implement HRR and BRCA testing early in the treatment pathway. Despite treatment advances, early testing is not routinely implemented in clinical practice. Barriers include unequal testing access, a lack of clarity on who, when, and how to test, and how to interpret test results accurately. These may prevent eligible patients from receiving treatment early. To address this, we combine our clinical experience with the current literature to support the wider adoption of HRR/BRCA testing by providing practical recommendations for implementing best practices along the PCa molecular testing pathway. Our recommendations aim to help identify suitable patients for early testing and guide how to obtain, interpret, and utilise molecular test results in clinical decision-making.

BACKGROUND:In the PSMAfore study, lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) significantly improved radiographic progression-free survival compared with change of androgen receptor pathway inhibitor (ARPI) in taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. Here, we present in-depth analyses of time to worsening of health-related quality of life (HRQOL) and pain, and time to first symptomatic skeletal events. METHODS:PSMAfore, an open-label, randomised, phase 3 trial, was conducted at 74 investigator sites (including hospitals with nuclear medicine departments and the research facilities where patients were recruited) across 14 countries. Eligible patients had metastatic castration-resistant prostate cancer, were candidates for ARPI change after one progression on a previous ARPI, had at least one PSMA-positive and no exclusionary PSMA-negative metastatic lesions by gallium-68 [68Ga]Ga-PSMA-11 PET-CT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (7·4 GBq; every 6 weeks for six cycles) or ARPI change (oral abiraterone or enzalutamide per local labelling). The primary endpoint was radiographic progression-free survival. Secondary endpoints included time to worsening in self-reported HRQOL (assessed using the Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EQ-5D-5L) and pain (assessed using the Brief Pain Inventory-Short Form [BPI-SF]) and time to the first symptomatic skeletal event. All analyses were done using the intention-to-treat principle. The study met the primary endpoint of radiographic progression-free survival (reported previously), and overall survival follow-up is ongoing; present analyses are from the third interim analysis of overall survival. This trial is registered with ClinicalTrials.gov, NCT04689828. FINDINGS:Between June 15, 2021, and Oct 7, 2022, 468 patients (426 [91%] were White and 12 [3%] were Black or African American) were randomly assigned to [177Lu]Lu-PSMA-617 (n=234) or ARPI change (n=234). Median follow-up time from randomisation to the third interim analysis data cutoff date (Feb 27, 2024) was 24·11 months (IQR 20·24-27·60) in the [177Lu]Lu-PSMA-617 group and 24·13 months (20·24-27·37) in the ARPI change group. [177Lu]Lu-PSMA-617 delayed time to worsening in all assessed FACT-P, EQ-5D-5L, and BPI-SF scales and subscales versus ARPI change. In the [177Lu]Lu-PSMA-617 versus ARPI change groups, median time to worsening in FACT-P total score was 7·46 months (95% CI 6·08-8·54) versus 4·27 months (3·45-4·50; hazard ratio [HR] 0·61 [95% CI 0·50-0·75]), in EQ-5D-5L utility score was 6·28 months (4·70-7·89) versus 3·88 months (3·25-4·44; 0·67 [0·54-0·82]), and in BPI-SF pain intensity was 5·03 months (4·40-6·80) versus 3·65 months (3·09-4·37; 0·72 [0·59-0·88]). [177Lu]Lu-PSMA-617 also delayed symptomatic skeletal events versus ARPI change: median time to first symptomatic skeletal event was not reached (95% CI not estimable [NE]-NE) in the [177Lu]Lu-PSMA-617 group versus 17·97 months (14·26-NE) in the ARPI change group (HR 0·41 [0·26-0·63]). The most common grade 3 or worse treatment-emergent adverse event was anaemia (14 [6%] of 227 patients in the [177Lu]Lu-PSMA-617 group vs 16 [7%] of 232 patients in the ARPI change group). There were no treatment-related deaths in the [177Lu]Lu-PSMA-617 group and one in the ARPI change group (cerebrovascular accident). INTERPRETATION:[177Lu]Lu-PSMA-617 might delay worsening of patient-reported outcomes and prevent symptomatic skeletal events versus ARPI change in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer whose disease has progressed once on a previous ARPI. FUNDING:Novartis.

Contexte L’étude Vision a montré que le [177Lu]Lu-PSMA-617 ajouté au standard de traitement prolongeait la survie sans progression (SSP) radiographique et la survie globale chez les patients (pts) atteints de cancer de la prostate résistant à la castration métastatique (CPRCm) TEP-PSMA positive. Les autorités françaises ont accordé une autorisation d’accès précoce au [177Lu]Lu-PSMA-617 dans cette indication. Méthodes Les pts CPRCm PSMA positif ayant reçu≥1 chimiothérapie à base de taxane et≥1 hormonothérapie dite de nouvelle génération (HTNG) ont été inclus. Le [177Lu]Lu-PSMA-617 a été administré jusqu’à 6 cycles (7,4 GBq) toutes les 6 semaines. Les caractéristiques des pts et la tolérance sont décrites pour l’ensemble de la population. L’efficacité a été analysée chez les pts inclus la 1re année. L’évaluation du grade des événements indésirables (EI) n’a pas été réalisée. Résultats Du 01/12/2021 au 30/06/2023, 945 pts ont été inclus et 535 ont été analysés pour l’efficacité. Au moment de la clôture des données, 474 pts étaient encore sous traitement et 471 avaient arrêté le traitement en raison d’une progression de la maladie (50,5 %), de la survenue d’un EI (7,2 %) ou d’un décès (7,4 %). 124 pts (26,3 %) ont bénéficié des 6 cures. Les caractéristiques de la population étaient : âge médian 73,2 (44–92) ans ; ECOG 0–1 : 86,3 % ; sites métastatiques : os 93,8 % ; ganglions lymphatiques : 62,4 % ; foie : 10,7 % ; traitement antérieur par taxane : 97,1 %, dont 61,6 %>1 ; traitement antérieur par HTNG : 100 % dont 66,6 %>1 (médiane : 2). Traitement concomitant par HTNG : 26,8 %. À propos des résultats d’efficacité, la meilleure réponse à l’imagerie a été évaluée à la discrétion des investigateurs : 1,2 % de RC, 35,7 % de RP et 26,7 % de maladie stable. Le PSA a diminué chez 68,1 % des pts avec un délai médian de 1,22 (0,1–9,6) mois. 12,8 % (n=121) des pts ont déclaré≥1 EI lié au traitement, dont 99 pts avec≥1 EI grave. Trois décès liés au traitement ont été rapportés. Les EI les plus rapportés étaient : thrombocytopénie (5,4 % des pts) et anémie (5,0 % des pts). Conclusion Dans cette cohorte « en vie réelle » de CPRCm traités par [177Lu]Lu-PSMA-617, comparativement à Vision, les pts sont plus lourdement prétraités, ont reçu moins de traitements par HTNG en concomitant et sont plus nombreux à avoir reçu>1 chimiothérapie par taxanes. La tolérance du [177Lu]Lu-PSMA-617 reste favorable. Les inclusions étant toujours en cours, des résultats actualisés seront présentés.

735 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy is the gold standard in localized muscle-invasive bladder cancer (MIBC), for fit patients. However, NAC is less prescribed in older patients, mainly due to safety concerns. This study aimed to evaluate the feasibility and efficacy of NAC for patients aged ≥ 75. Methods: We retrospectively included older patients, from 14 French GETUG centers. All patients had received at least one cycle of cisplatin-based NAC for localized MIBC, between 2010 and 2022. Primary outcome was NAC feasibility evaluated as the rate of patients that underwent optimal treatment, defined as at least 4 cycles of chemotherapy followed with local treatment (surgery or chemoradiotherapy). Secondary outcomes were NAC safety and efficacy. Results: 156 pts were included. Median age was 77 (from 75 to 96), with 20% aged ≥ 80. Patients were in good general condition: 54% were PS 0, with a median serum albumin level of 39 g/L, and 86% had a creatinine clearance ≥ 60 ml/min. 108 (69%) had a cT2N0 MIBC. 75 (48%) received dose dense MVAC (ddMVAC), 80 (51%) received gemcitabine-cisplatin (GC) and one patient received MVAC. 96 (62%) received an optimal treatment. 50 patients (32%) prematurely stopped NAC, due to death (3 pts, 2 from unknown causes), progressive disease (4), infection (3), toxicity (34 patients) mainly renal and hematological ones. Among them, 38 (76%) underwent local treatment. Among the 112 patients that underwent cystectomy, pathological complete response (pCR) was significantly more frequent when they received ≥ 4 cycles (36/78 = 46% versus 5/34 = 15%, p = 0.002). Median follow up from diagnosis was 28 months, with 97 patients (62%) that were still alive at the end of follow-up. Median disease-free survival was 3 years and 3 months. 2-years overall survival (OS) was 72%; 5-years OS was 56%. Conclusions: These data suggest that NAC for MIBC is feasible in selected older patients, even if toxicity was the main reason for cisplatin-based regimen discontinuation. Older patients who received optimal treatment were more often in pCR. OS in the this cohort of older patients was very similar to the results published in younger patients.

19 Background: Addition of abiraterone plus prednisone (AAP) to androgen deprivation therapy (ADT) with or without docetaxel (D) improved overall survival in men with de novo metastatic castration sensitive prostate cancer in PEACE-1 trial. An analysis of bone mineral density (BMD) was planned by an amendment in the last randomized patients to assess whether addition of AAP increases bone loss. Methods: Patients (pts) were randomized to receive either ADT + D + AAP or ADT + D (and also randomized for radiotherapy given to the prostate). BMD (g/cm2) of the lumbar spine (L), femoral neck (F) and total hip (H) were measured by dual x-ray absorptiometry at baseline, M6, M12 and M24 in both arms. Mean percent change in BMD values from baseline to the different time points were calculated. T-Scores were also assessed. Results: Among the 210 pts with BMD data, 182 (87%) had available data at baseline, 109 (52%) at M6, 94 (45%) at M12, and 109 (52%) at M24: 97 pts were treated with AAP and 98 without. In both arms, the median age was 65 years and 69 pts (71%) were ECOG PS 0. Median body mass index (BMI) was 25.6 and 26.5 kg/m2 in pts treated with or without AAP, respectively. BMD, T score and mean percent change in BMD values are summarized in the Table. Conclusions: This is the first prospective assessment of BMD in a randomized trial, according to an experimental treatment with AAP. Despite a bone loss increase in both arms over time, addition of AAP to ADT+D was associated with no or modest difference in bone loss during the first 2 years, compared to ADT+D. Data including fractures will be presented. Main limitations include the difficulty to reliably assess BMD in men with bone metastases, the limited sample size and the short follow-up (i.e. 2 years). Clinical trial information: NCT01957436. [Table: see text]

37 Background: PET imaging is not recommended for surveillance of mCSPC but it is used by some physicians. Little is known about surveillance for metastatic prostate cancer using PET imaging. The aim of this study was to assess the correlation between PSA response and PET imaging for mCSPC. Methods: An ambispective, multicentric, observational study, recorded PET imaging for patient’s treated with a minimum of 6 months of systemic therapy with androgen deprivation therapy (ADT) +/- androgen receptor pathway inhibitor (ARPI) +/- docetaxel for mCSPC with PSA < 0.2 ng/ml, normal CT scan and non progressive disease in bone scan. All of them had baseline evaluation with standard imaging. Results: Between August 2022 and September 2024, 57 patients (pts) with mCSPC were included, in 4 centres in France. Baseline characteristics at the time of metastatic disease were: median age of 65 years (range: 45-84), ISUP ≥4 for 63%, median PSA 22.1 ng/ml (1.6-5000ng/ml) with T≥3 in 53%. The majority of pts had low volume disease 56%, with synchronous metastatic disease for 67% and ≥ 4 bone metastases in 44%. Only 5 pts had visceral metastases. Pts were treated, by ADT + ARPI in 81%, ADT + docetaxel in 7% and triplet in 12% of cases. Patients had prostate radiotherapy (RxT) in 39% and RxT to metastatic bone lesion in 19%. The 8 months PSA was <0.2 ng/ml in 89% of pts. PET imaging was choline in 86%, PSMA in 14%. Median time between treatment initiation and PET imaging was 17 months and delay between PSA < 0.2 and PET imaging was 12 months (range: 0-32). A complete response was observed in 46 patients (81%). Non-complete responders (CR) were more frequently high volume disease (66%) and synchronous metastasis (100%), treated by ADT + ARPI alone (77%) or ADT + docetaxel (11%). Non CR were: 1 neuroendocrine progression, 1 lung cancer and 9 partial responders (2/9 progressed later). Conclusions: In patients with mCSPC, treated by ADT with ARPI and or docetaxel and with PSA < 0.2 ng/ml, a complete response is observed in 81 % when using PET imaging. The information given by PET imaging could be and additional surrogate measure to PSA response for intensification or de intensification the systemic and local treatment for mCSPC.

5034 Background: Since 2014, adaptation of chemotherapy based on tumor marker decline after the cycle of BEP (Bleomycin, Etoposide, Cisplatin) is a standard for patients with IGCCCG poor-risk NSGCT based on data from the GETUG-13 phase 3 trial (Fizazi et al, Lancet Oncol 2014; J Clin Oncol 2024). The aim of this multicenter study was to evaluate the GETUG-13 algorithm when used in routine practice. Methods: We collected data from all poor-risk NSGCT patients treated consecutively in 13 expert centers from 2013 to 2019. After one cycle of BEP, tumor marker levels were assessed at day 18-21. Pts with a favorable decline continued with BEP for 3 additional cycles (Fav group), whereas those with an unfavorable decline received up to 4 cycles of dose-dense chemotherapy (Unfav group). Data was analysed descriptively, and the Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Results: Data from 146 patients were collected (46 with PS ≥ 2, 35 with mediastinal NSGCT): 111 (76%) had an Unfav decline and 35 (24%) had a Fav decline. More pts with hCG > 50 000 UI/L and AFP > 10 000 were in the Unfav group (44.9% vs 17.6%, p=0.0045, and 26.9% vs 8.8%, p=0.0282). Surgery of residual masses was performed in 85.7% and 74.3% in the Fav and Unfav groups, and the procedure was complete in 83.3% and 59%, respectively. With a median follow-up of 5.8 years (95% CI,63.2-77.2), 5-year PFS rates were 68.6% (95% CI, 50.5-81.2) and 61.1% (95% CI, 51.2-69.6) in the Fav and Unfav groups, respectively. Five-year OS rates were 73.8% (95% CI, 55.6-85.4) and 64.6% (95% CI, 54.6; 73.0), respectively. In the short term, neuropathy, anemia and thrombopenia were more frequent in the Unfav group. Treatment-related deaths were reported in 2 (5.7%) and 5 (4.5%) (including 2 post-surgery deaths) pts in the Fav and Unfav groups, respectively. Peripheral neuropathy evolved favorably, with 4 (5.9%), 2 (3.8%) and no pts in the Unfav group reporting grade 3 toxicity at 6 months, 1 year and at last follow-up, respectively. Long-term side effects were infrequent with only one pt with grade 3 cardiovascular toxicity in the Unfav group. Late grade 2 toxicities included cardiovascular toxicity (1.4%), hypoacousia (1.4%), peripheral neuropathy (4.2%), chronic renal failure (CRF) (9.9%) in the Unfav group, and grade 2 CRF (8.3%) in the Fav group. In both groups, almost 80% pts had returned to work. Among pts with progression or relapse, salvage high-dose chemotherapy with stem-cell transplant was used in 4/11 (36.4%) and 13/33 (43.3%) in the Fav and Unfav groups, respectively. Conclusions: The GETUG-13 algorithm can be safely used in routine practice by expert centers, with a high cure rate similar to that reported in the original phase 3 trial and rare long-term toxicity. This data confirms that this algorithm is standard for poor-risk NSGCT.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) improved survival in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Patient‐reported symptoms in this context were poorly studied. The study aimed to compare symptom severity between patients and clinicians. Methodology The secondary analysis of the AMI clinical trial comparing changes in the gut microbiota in patients with la/mUC treated with pembrolizumab was conducted in nine French centers. Secondary endpoints were expected in this prospective study. Patient‐Reported Outcome‐Common Terminology Criteria for Adverse Events (PRO‐CTCAE) and CTCAE were assessed respectively by patients and clinicians before pembrolizumab initiation, and at each treatment visit until treatment cycle 12. Agreement in severity between clinicians and patients for grade ≥ 3 symptoms was calculated with Cohen's kappa coefficient. The toxicity index was generated for CTCAE and PRO‐CTCAE to assess discordance in a longitudinal manner. The Wilcoxon test was used to compare clinicians' and patients' toxicity index and symptom severity frequencies. Results Thirty‐nine patients were included (M/F sex ratio: 2.5) from December 2020 to March 2022. PRO‐CTCAE baseline completion rate was 77.5%. Cohen's kappa coefficient ranged from −0.017 (95% confidence interval (CI), [−0.039, 0.005]) for numbness/tingling to 0.161 (95% CI, [0.045, 0.276]) for fatigue. The patient self‐rated symptom toxicity index was > 2 for all symptoms compared to ≤ 0.62 (fatigue) when assessed by clinicians in longitudinal reporting of symptom frequency and severity with a p value < 0.001. The three most commonly reported symptoms by patients and clinicians, respectively, were: Fatigue 53.3% versus 23.4%, generalized pain 42.4% versus 16.5%, and insomnia 41.1% versus 9.5%. Symptom frequency reports between clinicians and patients were statistically different (p < 0.009). Conclusions Symptom severity assessment showed discordance between patients and physicians. Clinicians reported fewer symptoms and graded them less severely than patients. PROs should be used to accurately reflect patient experience. Trial Registration ClinicalTrials.gov identifier: NCT04566029

5071 Background: Late-line mCRPC has shown poor outcomes as a result of disease heterogeneity, metastases in bone and viscera including liver, and limited immunotherapeutic options. PT-112 is a novel therapy that inhibits ribosome biogenesis, induces robust immunogenic cell death, concentrates in bone and soft tissue, and previously exhibited clinical activity in patients (pts) with mCRPC. We report the results of a Phase 2 study of monotherapy PT-112 in the late-line mCRPC population. Methods: mCRPC pts with ≥3 prior standard of care treatments, including ≥1 androgen receptor pathway inhibitor (ARPI) and 1-2 taxanes with radiographic progression at entry were randomized to one of three dosing arms: Arm 1 (360 mg/m² Q2W), Arm 2 (250 mg/m² Q2W), and Arm 3 (360 mg/m² Q2W in cycle 1, then 250 mg/m² D15 of subsequent 28-day cycles). The primary endpoint was to determine the optimal dosing regimen based on safety and efficacy per FDA Project Optimus. Results: Pts on the study (N=111) had a median of 4 prior lines of therapy, 69% with ≥2 ARPis, 59% with 2 taxanes, and 24% with PSMA-Lu-177. At entry, pts had liver metastases (19%), bone-only metastases (28%), and evidence of bone progression (74%). The most common treatment-related adverse events (TRAEs) were fatigue (53%), nausea (42%), and anemia (41%); no G5 TRAEs. Discontinuation due to AEs was 12%. Due to superior balance of efficacy and tolerance at interim analysis, Arms 2 and 3 proceeded to full enrollment, while Arm 1 was discontinued. Safety and efficacy metrics are summarized in Table 1. In the more mature Arm 2, OS in pts without prior cabazitaxel (22 pts) was 16.4m and without cabazitaxel or PSMA-Lu-177 (17 pts) was 20.5m. 4% of pts had confirmed PCWG3 bone progression on study. A signal of immune response was observed via TCR sequencing with a statistically significant 20% increase in the percentage of TCR+ blood cells. Conclusions: PT-112 treatment resulted in a manageable and reasonably low rate of G3-4 TRAEs and was active in pts with very late-line mCRPC. The better balance of safety and efficacy in Arms 2 and 3 is indicative of an optimized RP3D. Biomarker responses (ALP, CTC and T cell) may reflect broad activity of PT-112. ctDNA analyses are ongoing. OS duration in these heavily pretreated patients, with low rates of bone progression and symptomatic skeletal events (SSEs) on study, are encouraging and supportive of a Phase 3 study of PT-112 vs standard of care. Clinical trial information: NCT02266745 . Study metrics. Metric Arm 1 (n=19) Arm 2 (n=46) Arm 3 (n=46) All Pts (N=111) G3-4 TRAEs (% of pts) 47 27 43 37 Adherence of dose regimen for first 2 cycles (% of pts) 42 59 67 59 Disease control rate (SD, PR, or CR) at 4 months (% of pts) 27 28 18 23 Median OS (m) 9.0 9.7 10.0 9.7 Median rPFS (m) 3.6 2.5 3.4 3.4 PSA50 (% of pts) 5 17 12 13 CTC0 (n, % of pts) 3/15 (20%) 5/22 (23%) 8/15 (53%) 16/52 (31%) ≥10% ALP decline (% of pts) 74 41 56 52 SSEs in first 4 months (% of pts) 16 4 2 5

825 Background: Pembrolizumab (Pb) is a treatment (trt) for advanced urothelial carcinoma (aUC). In this study, we analyzed the fecal metaproteome of aUC patients (pts) to investigate the differences in the taxonomic and functional composition of the gut microbiome in responders (R) vs non-responders (NR) to pembrolizumab monotherapy as second-line trt. Methods: We designed a prospective multicenter study in France. Stool samples were collected before and nine weeks after the start of Pb, with a maximum follow-up of 36 weeks. Trt efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors v1.1. Proteins were extracted from each sample and analyzed using high-resolution tandem mass spectrometry combined with liquid reverse phase chromatography. Raw data were interpreted without a priori assumptions. The R package Metacoder was used to analyze taxonomic diversity, while the mixOmics package was used to perform partial least squares discriminant analysis (sPLSDA) to reveal microbiota changes between R and NR pts. A Benjamini-Hochberg (BH)-corrected Wilcoxon test identified microbial functions with different frequencies in R and NR pts. A multivariate logistic regression analysis with Bonferroni correction was conducted to create a response-prediction classifier based on clinical variables and identified relevant microbial genera. The significance threshold was set at 5%. Results: From 2019 to 2022, 53 samples were taken from 34 different pts. Of these, 3 (8.8%) pts with complete response, 5 (14.7%) with partial response and 2 (5.9%) with stable disease were classified as R. Four (11.8%) deceased pts before response evaluation were excluded from the analysis. NR corresponded to disease progression in 20 pts (58.8%). No dysbiosis was detected. There were no statistically significant differences in alpha diversity over time or between R and NR. Beta diversity index showed microbiome stability at individual level during follow-up. sPLSDA at the genus level pooling all samples (before and after trt) showed a distinctive separation between R and NR (p ≤ 0.05). Of the genera contributing most to this separation, 4 genera were identified using logistic regression: Anaerostipes, Sutterella, Escherichia, Evtepia (adj. p ≤ 0.05). Functional composition analysis identified 31 signaling pathways that differ between R and NR. These signaling pathways were clustered highlighting 7 functions that differed between R and NR when modulated by Pb. Host function analysis identified the “response to external biotic stimuli” signaling pathway significantly associated to R (BH adj p-value ≤0.05). Conclusions: The composition of the gut microbiome and metabolic functions differed between R and NR pts with aUC under Pb. The genera Anaerostipes , Sutterella, Escherichia and Evtepia could be biomarkers for the efficacy of pembrolizumab. Clinical trial information: NCT03584659 .

This article aims to report the recommendations from the French society for radiation oncology (Société française de radiothérapie oncologique, SFRO) on the use of external beam radiotherapy in the management of testicular cancer. Testicular cancers account for 1 % of adult neoplasms yet represent the most frequently diagnosed urological tumour in young men. Most of testicular cancers (95 %) are germ cell tumours, which include both seminomatous and non-seminomatous tumours. Surveillance is the preferred option for stage I seminoma following orchidectomy, but adjuvant chemotherapy or para-aortic radiotherapy remain possible options. For stages IIA/IIB seminoma, either chemotherapy or para-aortic and ipsilateral iliac nodal areas irradiation can be proposed. In non-seminomatous tumours, chemotherapy is the standard treatment. Target volumes, doses, fractionation regimens, and considerations for organs at risk are discussed. Follow-up recommendations are provided, aiming to ensure both early detection of cancer recurrence and late treatment-related side effects. These guidelines highlight the importance of a multidisciplinary approach for the management of germ cell tumours as well as careful consideration of long-term toxicities, in this young patient population with a long-life expectancy.

PURPOSE:Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in BRCA2. PARP inhibitors (PARPi) are standard treatments for BRCA1/2-altered patients with mCRPC, and evidence for platinum agents is limited. This study assesses single-agent platinum therapy in patients with mCRPC with and without DDR alterations. METHODS:This multicenter, retrospective study included patients with mCRPC with known DDR status treated with platinum monotherapy. DDR-positive (DDR+) patients had deleterious germline or somatic alterations in DDR genes (BRCA1, BRCA2, CDK12, ATM, CHEK2, PALB2, or FANCA), whereas DDR-negative (DDR-) patients had no such alterations. Prostate-specific antigen (PSA) response, progression-free survival (PFS, PSA/clinical/radiographic), and overall survival (OS) were assessed in DDR+ and DDR- groups. RESULTS:Among 129 patients, 81 had DDR+ and 48 had DDR- cancers. A PSA decline of ≥50% was demonstrated in 48% in BRCA, 9% in DDR+ non-BRCA, and 13% in DDR- patients (P < .0001). Objective responses occurred in 37.5% in BRCA, 11% in DDR+ non-BRCA, and 13% in DDR- patients (P = .017). No response was reported in DDR+ patients who had received previous PARPi (n = 16). The median PSA response was 5 months for BRCA, 2 months for DDR+ non-BRCA, and 1.7 months for DDR- patients, respectively (P = .015), whereas the median clinical/radiographic PFS was 4.7 months, 2.8 months, and 2 months, respectively (P = .2). In PARPi-naïve patients, the median OS was 13.7 months for BRCA, 8.7 months for DDR+ non-BRCA, and 6.1 months for DDR- patients (P = .013). CONCLUSION:Single-agent platinum agents show significant anticancer activity in BRCA-mutated patients with mCRPC without previous PARPi exposure. With their low cost and broad availability, platinum agents offer a practical alternative, particularly in regions where PARPi are inaccessible.