Javier Molina-Cerrillo

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.

Background: Renal Cell Carcinoma (RCC) represents a growing global health burden, with rising incidence and mortality worldwide. Despite major therapeutic advances, access to novel systemic treatments remains uneven across countries and regions. Methods: We conducted a cross-sectional, web-based international survey to assess the availability and reimbursement status of 20 innovative systemic therapies for RCC. Responses were collected from 144 clinicians, including medical oncologists, radiation oncologists, urologists, and nuclear medicine specialists, across 58 countries. Analyses examined associations between national income level, gross domestic product (GDP), and treatment availability. Findings: Thirty-six percent of the countries analyzed had at least 15 of the 20 therapies available. Full reimbursement for at least 15 of the selected innovative therapies was reported in six countries (10%), while 21 countries (36%) fully reimbursed 10-14 therapies and 13 countries (23%) reimbursed 1-9 therapies. In contrast, no full reimbursement for any of the assessed therapies was reported in 18 countries (31%). Higher national income level was significantly associated with greater availability of innovative therapies (Kruskal–Wallis test, P < .0001). Armenia (0.709), Greece (0.685), and Israel (0.666) exhibited the highest GDP-adjusted Drug Availability Index (DAI), whereas India (5.195), Nigeria (4.612), and Morocco (3.794) demonstrated the greatest number of available therapies per US$1000 of GDP per capita. Interpretation: Access to innovative systemic therapies for RCC remains highly unequal at the global level, with reimbursement posing a major barrier even where drugs are available. Internationally coordinated efforts addressing health policy, infrastructure, and equitable pricing are urgently required to ensure that advances in RCC treatment translate into improved outcomes for patients across diverse economic settings.

Background/Objectives: Despite advances in metastatic renal cell carcinoma (mRCC), long-term survival is poor and biomarkers are lacking. Optimal integration of cytoreductive nephrectomy (CN) in the current era remains controversial. CABOPRE, the first phase II trial assessing perioperative cabozantinib in mRCC patients eligible for CN, aimed to determine its effects in this setting, integrating tumor outcomes with molecular profiling. Methods: CABOPRE (NCT06377722) is a multicentre, single-arm, phase II study conducted in Spanish academic hospitals. Patients with resectable metastatic clear cell RCC (ccRCC) eligible for post-treatment CN received perioperative cabozantinib (60 mg/day for 12 weeks; n = 18). The primary endpoint was the objective response rate (ORR) at 12 weeks assessed by RECIST v1.1. Exploratory analyses included longitudinal plasma miRNA and spatial transcriptomic profiling to identify candidate biomarkers. The trial closed early because of slow accrual, after enrolling 18 of 50 planned patients and without completing the 26-patient first stage of the Simon two-stage design; the planned interim analysis was therefore never performed. Results: Because the two-stage design was not completed, the primary endpoint could not be formally evaluated against the prespecified decision rule. Among 15 evaluable patients, the objective response rate was 26.7% (95% CI, 7.8–55.1), with stable disease in 10 (66.7%) and progressive disease in 1 (6.7%). Cabozantinib demonstrated a manageable safety profile (Grade 1–2 adverse events). In exploratory biomarker analyses, miR-126-3p upregulation and VEGFA/CCND1 downregulation were associated with tumor shrinkage, and the adhesion molecules ITGAV and ICAM1 were upregulated in these patients. Because no direct vascular measurements were performed, these changes are described as treatment-associated and hypothesis-generating rather than as predictors of response or evidence of vascular normalization. Conclusions: The observed response rate was close to the 25% null rate, and the prespecified efficacy rule could not be applied. CABOPRE provides preliminary evidence that perioperative cabozantinib is active and represents a viable backbone for neoadjuvant combination strategies in selected patients with potentially resectable mRCC. The identified molecular heterogeneity and stromal-immune signatures provide a biological rationale for the prospective evaluation of cabozantinib-IO combinations in this setting.

Neuroendocrine tumors are a rare and heterogeneous group of neoplasms that frequently cause carcinoid syndrome, characterized by diarrhea, flushing, and carcinoid heart disease. A recent therapy for carcinoid syndrome involves inhibition of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, using telotristat ethyl. Telotristat has demonstrated clinical control of carcinoid syndrome; however, its potential antitumoral effects remain unclear. This study aimed to evaluate the antitumor activity of telotristat ethyl alone and in combination with everolimus in neuroendocrine tumor models. Cell viability was assessed in three neuroendocrine tumor cell lines of pancreatic (BON-1, QGP-1) and intestinal (HROC57) origin following treatment with telotristat ethyl. Combination treatments with telotristat ethyl and everolimus or other antitumoral agents were evaluated for effects on cell viability, apoptosis, and cell cycle distribution. In vivo efficacy was examined in nude mice bearing BON-1-derived xenografts treated with telotristat ethyl, everolimus, or the combination. Tumor growth, toxicity, proliferation (Ki67), and apoptosis (active caspase-3) were analyzed. Telotristat ethyl reduced cell viability in all three neuroendocrine tumor cell lines. Combination with everolimus, but not with other antitumoral treatments, synergistically decreased cell viability, induced apoptosis, and reduced the proportion of cells in the G2/M phase. In nude mice bearing BON-1 xenografts, combined treatment with telotristat ethyl and everolimus arrested tumor growth without signs of toxicity compared with single treatments. At the end of treatment, tumors from combination-treated mice showed a reduction in proliferation (Ki67) comparable to single-treated groups and an increase in apoptosis as indicated by active caspase-3. Telotristat ethyl exhibits antitumoral activity in neuroendocrine tumor models in vivo. Moreover, the combination of telotristat ethyl and everolimus, two therapies already used in clinical practice, may represent a safe and effective therapeutic strategy for neuroendocrine tumors.

Background: Anaplastic thyroid cancer (ATC) is an extremely rare cancer with very poor prognosis. Targeted therapies have improved outcomes in selected patients, but molecular testing is often difficult because of the aggressive course, rapid clinical deterioration, and long turnaround times. This study aimed to provide real-world evidence on the management and outcomes of ATC and to evaluate the prognostic impact of molecular testing. Materials and Methods: This multicentric, retrospective study included patients diagnosed with ATC between 1992-2024 from the REGETNE-Thyroid Network. Factors associated with overall survival (OS) were analyzed using Cox proportional hazards models. Results: 214 patients were included (median age 70.8 years; 56.5% female). Median OS was 4.5 months. Access to molecular testing (HR 0.42, p = 0.001) and BRAF V600E mutation (HR 0.50, p = 0.008) were associated with longer OS, whereas TERT promoter mutations were associated with shorter survival (HR 2.80, p = 0.014). Local surgery showed a favorable prognostic association, regardless of stage (IVa/IVb: HR 0.54, p = 0.026; IVc: HR 0.36, p < 0.001). In metastatic disease, immunotherapy (HR 0.31; p < 0.001), tyrosine kinase inhibitors (HR 0.40; p = 0.002) and their combination (HR 0.24; p = 0.001) significantly improved OS, whereas chemotherapy did not (HR 0.76; p = 0.096). Targeted therapy, used predominantly (>95%) in BRAF V600E-mutated ATC, was also associated with longer survival (HR 0.40; p = 0.001). Conclusion: Molecular testing was associated with improved survival in ATC, likely driven by the identification of actionable alterations with effective targeted therapies. Local management is key in all stages. Our findings also support immunotherapy, tyrosine kinase inhibitors and their combinations as key therapeutic options.