Sarah Scagliarini

Background: Homologous recombination repair (HRR) testing is increasingly relevant in prostate cancer because it identifies patients who may benefit from biomarker‐guided treatment strategies, including poly(ADP‐ribose) polymerase inhibitors (PARPi). However, real‐world implementation of HRR testing remains variable across countries and clinical settings, and the extent to which current testing pathways capture actionable alterations is not well defined. Methods: ARON‐3 is a multinational, multicentre, retrospective real‐world study of patients with prostate cancer. In this subanalysis, we assessed genomic testing uptake within the overall ARON‐3 cohort and characterised HRR testing pathways and detected pathogenic alterations among patients with available genomic results. Genomic testing included germline, somatic tumour, and/or circulating tumour DNA (ctDNA) assays performed in routine practice across participating centres. Multivariable logistic regression was used to identify clinicopathologic factors associated with undergoing genomic HRR testing. Results: Among 2,192 patients included in ARON‐3, genomic testing results were available for 719 (33%). Among tested patients, 660 (92%) underwent germline testing and 610 (85%) somatic testing; 549 (77%) underwent both, whereas 109 (15%) had germline‐only and 61 (8%) somatic‐only testing. In multivariable analysis, metastatic castration‐resistant prostate cancer, high‐volume disease, and Gleason score > 8 were independently associated with higher odds of testing, while age ≥ 70 years was associated with lower odds of testing. Overall, 238 tested patients (33%) harboured pathogenic HRR alterations, corresponding to 11% of the entire ARON‐3 cohort. Somatic pathogenic alterations were more frequent than germline alterations. BRCA2 was the most frequently altered gene, while non‐BRCA1/2 alterations were also detected, particularly in centres using broader multigene panels. Most centres relied on BRCA1/2 ‐focused assays, and the use of liquid biopsy remained limited. Conclusions: This multinational real‐world analysis demonstrates substantial heterogeneity in HRR testing uptake and testing pathways across participating ARON‐3 centres. Testing was more commonly performed in patients with more advanced disease features, suggesting that clinically relevant subgroups may still be differentially selected for genomic assessment. Broader and more standardised implementation of comprehensive HRR profiling may improve the identification of actionable alterations and strengthen precision medicine in prostate cancer.

Non-conventional prostate cancer histologies represent a small but clinically significant subset characterized by aggressive behavior, atypical biomarker profiles, and reduced dependence on androgen receptor signaling. Evidence indicates these histologies reflect dynamic biological states driven by genomic instability, lineage plasticity, and therapeutic selection rather than static morphologic entities, with several morphologies acting as accessible, if imperfect, surrogates for actionable alterations. We performed a translational narrative review integrating anatomic pathology, genomic and epigenomic biology, and biomarker-selected therapy, searching PubMed/MEDLINE, Embase, Cochrane CENTRAL, the ASCO Meeting Library, ESMO publications, and APCCC through May 2026, spanning neuroendocrine, ductal, intraductal, cribriform, adenosquamous, sarcomatoid, adenoid cystic, signet ring cell, and mucinous subtypes. These histologies are individually uncommon but are consistently associated with advanced stage and inferior survival. Neuroendocrine prostate cancer is the most aggressive phenotype and a major mechanism of resistance to AR-directed therapy, driven by combined RB1 and TP53 loss, epigenetic reprogramming, and lineage plasticity, and marked by DLL3 expression. Cribriform and intraductal carcinoma are often enriched for BRCA2 and DNA-repair deficiency, whereas ductal differentiation is associated with mismatch-repair deficiency in a subset, with implications for PARP inhibition and checkpoint blockade. Emerging strategies include platinum-based chemoimmunotherapy and investigational lineage-directed agents targeting DLL3, STEAP1, KLK2, and TROP-2, alongside radioligands. These histologies are best viewed as biologically distinct, evolving disease states. By integrating pathology, molecular biology, and biomarker-selected therapy into one translational pathway, this review reframes non-conventional histology as a prompt for early molecular characterization and adaptive, biology-driven treatment.

Background: Immune checkpoint inhibitor–tyrosine kinase inhibitor combinations represent a standard first-line option for metastatic renal cell carcinoma (mRCC). However, patients enrolled in pivotal trials often differ from those treated in routine practice. We report real-world outcomes of pembrolizumab plus axitinib within the Campania Oncology Network. Methods: We conducted a multicenter retrospective study including consecutive treatment-naïve mRCC patients who received first-line pembrolizumab plus axitinib between January 2021 and November 2023 across eight regional centers. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate (ORR) and safety. Results: A total of 117 patients were included. IMDC risk was favorable in 19.6%, intermediate/poor in 65%, and unknown in 15.4%. Median age was 59 years, and 53.8% had ECOG performance status ≥ 1. Clear-cell histology accounted for 87.2% of cases; brain metastases were present in 36%. After a median follow-up of 12.8 months, median PFS was 15.1 months (95% CI 9.6–NR), and median OS was not reached. ORR was 27.3%, with a disease control rate of 79.5%; patients with non-clear-cell histology showed an ORR of 41.7%. Disease progression was the main cause of treatment discontinuation (49%), while adverse events (AEs) led to discontinuation in 6% of cases. Grade ≥3 AEs occurred in 14% of patients. Most toxicities were grade 1–2, including diarrhea (23.9%), asthenia (18%), hypothyroidism (12.8%), and hypertension (9.4%). Grade 1–2 AEs were significantly more frequent in females compared with males (57.6% vs. 35.7%, p = 0.05). Conclusions: In this consecutive regional cohort, pembrolizumab plus axitinib showed clinically relevant disease control, although ORR was lower than in pivotal trials. Performance status emerged as a key prognostic factor. Real-world data from oncology networks may support personalized first-line treatment decisions in mRCC.

The Meet-URO score provided a more accurate prognostication than the international metastatic RCC database consortium (IMDC) risk group classification for patients with metastatic renal cell carcinoma (mRCC) by incorporating the pretreatment neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases in different settings of the disease. To additionally validate the Meet-URO score on overall survival (OS) in a cohort of mRCC patients treated with first-line pembrolizumab plus axitinib, a post hoc analysis of the observational prospective ProPAXI study was conducted. Progression-free survival (PFS) was also considered. Harrell’s C-index was used to compare the discriminative ability on OS and PFS. Overall, the ProPAXI study included 170 patients. Both the five- and the three-risk group Meet-URO score were evaluated to account for the small sample size. The five Meet-URO risk group score showed a mOS of 27.1 months (p = 0.064) and 10.3 (p = 0.014) months for group 4 and group 5, respectively, while it was not reached for the other groups (p < 0.01). Although a worsening of PFS was observed with increasing the risk group, these differences were not statistically significant (p =0.19). Similar results were observed fot the three-risk group Meet-URO score. Both five and the three Meet-URO risk groups showed a better C-index for OS (0.69 and 0.66, respectively) compared to IMDC (0.62) and for PFS (0.60 and 0.59, respectively) compared to IMDC (0.56). These findings suggest that the Meet-URO score may provide more accurate prognostic stratification than IMDC alone in mRCC patients treated with first-line pembrolizumab and axitinib.

PURPOSE: Sarcomatoid renal cell carcinoma (sRCC) represents a kidney malignancy with a sarcomatoid component associated with poor prognosis. Immunotherapy (IO)-based combinations demonstrated promising activity in sRCC, yet real-world evidence (RWE) remains limited. We aimed to characterize the clinicopathologic features and outcomes of patients with metastatic sRCC treated with first-line immune-based combinations. PATIENTS AND METHODS: This retrospective analysis from the ARON-1 study included 350 patients with histologically confirmed metastatic sRCC treated with first-line IO + IO, or IO + tyrosine kinase inhibitor across 66 centers in 21 countries (2016-2024). Overall survival (OS) was analyzed using Kaplan-Meier and Cox regression methods. Correlations between 2-year OS and clinical variables were assessed using Pearson's coefficient. RESULTS: After a median follow-up of 19.1 months, median OS was 26.9 months (95% CI, 21.6 to 43.3). OS was longer in males (43.3 v 15.3 months in females; P < .001), in whom underwent nephrectomy (32.3 v 20.7 months; P = .002), and in patients without hepatic (32.3 v 15.3 months; P < .001), without skeletal (41.0 v 20.0 months; P = .007), or without lymph node metastases (43.3 v 24.6 months; P = .037). Median OS varied by International Metastatic RCC Database Consortium (IMDC) risk group: 66.5, 29.4, and 11.7 months in favorable-, intermediate-, and poor-risk patients, respectively ( P < .001). Different IO regimens showed variable outcomes by risk subgroup. Limitations include retrospective design and lack of central pathology review. CONCLUSION: First-line IO-based combinations provide clinically meaningful survival in sRCC, with outcomes affected by sex, metastatic sites, and IMDC risk. This RWE may support a tailored therapeutic approach on the basis of baseline prognostic factors.

Background: Cabozantinib use in everyday clinical practice for advanced or metastatic renal cell carcinoma (RCC) is relatively recent, and real-world data on treatment persistence, adherence and sequencing are still limited. Methods: We conducted an analysis based on an integrated administrative database, covering around 6.9 million health-assisted Italian individuals, to explore the use of cabozantinib for RCC. Patients with at least one prescription for cabozantinib during 2017-2020 were searched. These were characterized during all available period (i.e. from 2010 onwards) before the index date and were observed after inclusion. Results: A total of 113 patients treated with cabozantinib in second or subsequent line were included, and their demographic, clinical and treatment characteristics were described. About half of these RCC patients were aged >65 years (47.8%). Sixty patients (53.1%) were highly adherent to cabozantinib therapy, and the median cabozantinib treatment duration of use was 8.7 months (95% confidence interval: 5.8-11.1). During the first year of follow-up, the average total cost per patient was €32,508. Conclusions: We described second or subsequent line cabozantinib treatment for RCC in a real-world setting and the economic burden of disease in Italy, taking advantage of large, integrated administrative databases.

Background: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022. Methods: We searched PubMed RCTs testing novel therapies in genitourinary (GU) cancers and published in fifteen selected journals (Annals of Oncology, BMC Cancer, British Journal of Cancer, Cancer Discovery, Clinical Cancer Research, Clinical Genitourinary cancer, European Journal of Cancer, European Urology, European Urology Oncology, JAMA, JAMA Oncology, Journal of clinical Oncology, Lancet, Lancet Oncology and The New England Journal of Medicine). We excluded trials investigating exclusively best supportive care or behavioral intervention, as well as subgroup or post hoc analyses of previously published trials. For each RCT, we investigated whether HRQoL assessment was performed by protocol and if results were reported in the primary manuscript or in a secondary publication. Results: We found 85 eligible trials published between 2010 and 2022. Only 1/85 RCTs (1.2%) included HRQoL among primary endpoints. Of note, 25/85 (29.4%) RCTs did not include HRQoL among study endpoints. HRQoL results were non-disclosed in 56/85 (65.9%) primary publications. Only 18/85 (21.2%) publications fulfilled at least one item of the CONSORT-PRO checklist. Furthermore, 14/46 (30.4%) RCTs in prostate cancer, 12/25 (48%) in kidney cancer and 3/14 (21.4%) in urothelial cancer reported HRQoL data in primary publications. Next, HRQoL data were disclosed in primary manuscripts of 12/32 (37.5%), 5/13 (38.5%), 5/16 (31.3%) and 5/15 (33.3%) trials evaluating target therapies, chemotherapy, immunotherapy and new hormonal agents, respectively. Next, we found that HRQoL data were reported in 16/42 (38%) and in 13/43 (30.2%) positive and negative trials, respectively. Finally, the rate of RCTs reporting HRQoL results in primary or secondary publications was 55.3% (n = 47/85). Conclusions: Our analysis revealed a relevant underreporting of HRQoL in RCTs in advanced GU cancers. These results highlight the need to dedicate more attention to HRQoL in RCTs to fully assess the value of new anticancer treatments.