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Patients with metastatic urothelial carcinoma (mUC) are typically elderly and often have other comorbidities that require the use of concomitant medications. In our study we evaluated the association of concomitant use of antibiotics (ATBs), proton pump inhibitors (PPIs), corticosteroids, statins, metformin and insulin with patient outcomes and we validated the prognostic role of a concomitant drug score in mUC patients treated with enfortumab vedotin (EV) monotherapy. Data from 436 patients enrolled in the ARON-2 EV retrospective study were analyzed according to the concomitant medications used at baseline. Finally, the patients were stratified into three risk groups according to the concomitant drug score based on ATBs, corticosteroids and PPIs. Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Inferior survival outcomes were observed in ATB users compared to non-users (OS: 7.3 months, 95%CI 5.0 - 12.3 vs 13.7 months, 95%CI 12.2 - 47.3, p = 0.001; PFS: 5.1 months 95%CI 3.3 - 17.7 vs 8.3 months, 95%CI 7.1 - 47.3, p = 0.001) and also in corticosteroid users compared to non-users (OS: 8.4 months, 95%CI 6.6 - 10.0 vs 14.2 months, 95%CI 12.7 - 47.3, p < 0.001; PFS: 6.0 months 95%CI 4.6 - 7.9 vs 8.9 months, 95%CI 7.2 - 47.3, p = 0.004). In the Cox multivariate analysis, the concomitant drug score was a significant factor predicting both OS (HR = 1.32 [95% CI 1.03 - 1.68], p = 0.026) and PFS (HR = 1.23 [95% CI 1.01 - 1.51], p = 0.044). Our findings suggest detrimental impact of concomitant use of ATBs and corticosteroids on survival outcomes and the prognostic utility of the concomitant drug score in previously treated mUC patients receiving EV., Competing Interests: Declarations. Conflict of interest: Ondrej Fiala received honoraria from Roche, Janssen, GSK and Pfizer for consultations and lectures unrelated to this project. Sebastiano Buti received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. All unrelated to the present paper. Alfonso Gómez de Liaño has received honoraria for advisory boards, consultation, or educational events from AAA HealthCare, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Johnson & Johnson, MSD, Merck KGaA, Novartis, Recordati Rare Diseases and Roche (all unrelated to the present paper); and has Institutional research funding from AstraZeneca, Genmab A/S, Gilead Sciences, Johnson & Johnson, Merck KGaA, MSD, Roche and Syneos Health. Takahiro Kimura is a paid consultant/advisor of Astellas, AstraZeneca, Bayer, Janssen, Sanofi, and Takeda. Martin Angel received honoraria from Roche, Johnson & Johnson, Raffo and Pfizer for consultations and lectures unrelated to this project. Javier Molina-Cerrillo: reports research funding from Roche, Ipsen, Pfizer, and Janssen; travel support from Pfizer, Janssen, Ipsen, and BMS; a consulting or advisory role with Ipsen, Roche, BMS, Pfizer, Sanofi, Janssen, Astellas, Eisai, Adium and MSD. All unrelated to the present paper. Maria T Bourlon is a consultant of Bristol Myers Squibb, Merck, MSD, Gilead, Astellas and Asofarma and a speaker for Janssen Pharmaceuticasl, MSD, Merck, and Astellas. All unrelated to the present paper. Andrey Soares: Honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, Adium. Consulting or Advisory Role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, Pfizer, Novartis. Research Funding from Bristol-Myers Squibb (Inst), Astellas (Inst), AstraZeneca (Inst). Travel, Accommodations, Expenses from Bayer, Janssen, Ipsen, Adium, MSD, Merck Serono. Ownership: BIO, Brazilian Information Oncology. All are unrelated to this study. Nonfinancial with no other potential conflicts of interest were reported. Yüksel Ürün has served on advisory board for Abdi-İbrahim, Astellas, AstraZeneca, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen ilaç, Gilead, GSK, Janssen, Merck, MSD, Novartis, Pfizer, Roche and received travel grants, honoraria or consultation fees from Abdi-İbrahim, Astellas, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen İlaç, Gilead, GSK, Janssen, Merck, Novartis, Pfizer and Roche. All unrelated to the present paper. Bohuslav Melichar has received honoraria from Roche, BMS, MSD, Novartis, Merck Serono, Eli Lilly, Pfizer, and AstraZeneca, all unrelated to the present paper. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Vincenza Conteduca has served as a consultant/advisory board member for Johnson&Johnson, Astellas, Merck, AstraZeneca, Amgen, EISAI, Recordati, Novartis, and Bayer and has received speaker honoraria or travel support from Astellas, Johnson&Johnson, Ipsen, Bayer, Gilead, and BristolMyers Squibb. Fernando Sabino M. Monteiro: Research support was provided by Merck Sharp Dome. Honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome. Ownership: BIO, Brazilian Information Oncology. All are unrelated to this study. Tomas Buchler has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, Roche, Astellas, Merck, Eisai, Merck Sharp Dohme, Novartis, AstraZeneca, Janssen, and Pfizer, all unrelated to this project. Francesco Massari has received research support and/or honoraria from Advanced Accelerator Applications, Astellas, Astra Zeneca, Bayer, BMS, Janssen, Ipsen, MSD, Pfizer outside the submitted work. Javier Molina-Cerrillo declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. JMC has received research grants from Pfizer, IPSEN and Roche. Shilpa Gupta is a consultant for Bristol Myers Squibb, Merck, Pfizer, Gilead, Bayer, Seattle Genetics, is speaker for Bristol Myers Squibb and has Institutional research funding from Seatte Genetics, Pfizer, Merck, Bristol Myers Squibb, Roche, Novartis, Tyra Biosciences. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas and Bayer, all unrelated to the present paper. Other authors declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Ethical approval: The study protocol was approved on September 28, 2023, by the Ethical Committee of the coordinating center (Marche Region-Italy-No. 2022 39/7875, Study Protocol “ARON 2 Study” NCT05290038) and by the Institutional Review Boards of participating centers. Consent to participate: The Informed consent with subsequent analysis of the follow-up data was obtained from all participants. Consent for publication: All authors have approved the manuscript for publication., (© 2025. The Author(s).)

Background and Objective: Circulating tumor DNA (ctDNA) testing provides valuable prognostic and predictive information for guiding therapeutic choices and monitoring disease progression and drug resistance for urological tumors. Our review focuses on emerging opportunities for ctDNA analysis in urological tumors and the development of potential circulating biomarkers within a multidisciplinary framework to improve personalized treatment., Methods: A nonsystematic literature review was conducted in the PubMed and MEDLINE databases. Prospective and retrospective peer-reviewed studies, review articles, and research abstracts on the use of ctDNA for urological tumors were included., Key Findings and Limitations: Several studies have demonstrated that ctDNA analysis is a promising tool that can help clinicians in the diagnosis and clinical management of urological tumors. In prostate and urothelial cancers, the ctDNA fraction increases proportionally from localized to metastatic disease, indicating a higher tumor burden and more aggressive behavior. Thus, ctDNA seems to be a useful tool for improving prognostic risk stratification and treatment selection. Data on the use of liquid biopsy in renal cell carcinoma are still limited, and assessment of prognostic and predictive biomarkers is a critical unmet need., Conclusions and Clinical Implications: ctDNA analysis promises to revolutionize the management of urological tumors in different disease settings. Integration of ctDNA testing in routine clinical practice will require a multidisciplinary approach that involve patients, clinicians, and molecular biologists., Patient Summary: We reviewed how testing for tumor DNA in blood (circulating tumor DNA, ctDNA) is used in urological cancers. A great deal of evidence supports the usefulness of this noninvasive test. However, further research via a multidisciplinary approach is needed before ctDNA testing becomes part of routine patient care., (Copyright © 2024. Published by Elsevier B.V.)

The definition of "non-metastatic hormone-sensitive prostate cancer" (nmHSPC) can be applied to patients with prostate cancer (PC) who are androgen-deprivation therapy-naïve and without evidence of metastatic disease. This definition includes heterogeneous situations; however, PC patients at high risk of metastatic spread - and who have not started a hormonal treatment - constitute a unique category with unmet clinical needs. This narrative review critically discusses the advances that characterize the rapidly evolving diagnostic and therapeutic scenario in the nmHSPC setting. We found that nmHSPC represents a grey zone in the context of PC. New clinical trials are trying to redefine the therapeutic algorithm of these patients, but escalating treatment seems not to be the right choice for the overall population. Biomarkers able to stratify patients - including molecular ones - are urgently needed, and biomarker-based clinical trials could clarify their prognostic and predictive role in the nmHSPC scenario., Competing Interests: Declaration of Competing Interest Emilio Francesco Giunta received personal fees from Novartis and travel accommodation from Janssen and Bayer. Giandomenico Roviello received honoraria for advisory boards or invited speaker fees from BMS, Astellas, Bayer, Ipsen, Novartis, Roche, and AstraZeneca. Vincenza Conteduca: received honoraria for advisory boards or speaker fees from Janssen, Astellas, Merck, AstraZeneca, 'Ipsen, Bayer, Novartis, Recordati, BMS, MSD, GSK. Elena Verzoni received honoraria for advisory boards or speaker fees from MSD, Pfizer, Astellas, BMS, AstraZeneca, Ipsen and Janssen. Giuseppe Procopio services advisory boards/consulting for Astellas, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Brystol Myers, BMS, Janssen, EISAI, Ely Lilly, Janssen, IPSEN, Menarini, Merk, MSD, Novartis, Roche, Pfizer. Ugo De Giorgi received honoraria for advisory boards or speaker fees for Pfzer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Roche, Novartis, Clovis, GSK, AstraZeneca, institutional research grants from AstraZeneca, Sanofi and Roche, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells., (© 2024. The Author(s).)

Introduction: The administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC)., Patients and Methods: Total 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as "no concomitant PPIs (PPI-)" if no PPIs were administered during TKIs, and as "concomitant PPIs (PPI+)" if the administration of PPIs was at least 75% of the time during which TKIs were given., Results: Eighty patients administered pazopanib were PPI- and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI- (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI- (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI- (6 months vs. not reached, P = .04). No correlation with adverse events was found., Conclusions: This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use., Competing Interests: Disclosure CP acted as a consultant and/or a speaker for Angelini Pharma, Biorek, BMS, Eisai, General Electric, Ipsen, Medendi, and MSD, and as a protocol steering committee member for BMS, Eisai, and MSD. MR received honoraria as a speaker/consultant by Astra Zeneca, MSD, BMS, Janssen, Merck and Gilead. MDR received fees from Astellas, AstraZeneca, Celgene, Novartis, Pfizer, Bio-Rad, Janssen, Sanofi-Aventis, Roche, and Ipsen; RD reports receiving speaker bureau/advisor's fee from Ipsen, Novartis, Pfizer, Sanofi Genzyme, AstraZeneca, Janssen, Gilead, Lilly, Gilead, and EUSA Pharma. All other authors have declared no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan-Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11-3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11-3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials.

DNA-damage repair (DDR) pathways alterations, a growing area of interest in oncology, are detected in about 20% of patient with prostate cancer and are associated with improved sensitivity to poly(ADP ribose) polymerases (PARP) inhibitors. In May 2020, the Food and Drug Administration (FDA) approved two PARP inhibitors (olaparib and rucaparib) for prostate cancer treatment. Moreover, germline aberrations in DDR pathways genes have also been related to familial or hereditary prostate cancer, requiring tailored health-care programs. These emerging scenarios are rapidly changing diagnostic, prognostic and therapeutic approaches in prostate cancer management. The aim of this review is to highlight the five W-points of DDR pathways in prostate cancer: why targeting DDR pathways in prostate cancer; what we should test for genomic profiling in prostate cancer; "where" testing genetic assessment in prostate cancer (germline or somatic, solid or liquid biopsy); when genetic testing is appropriate in prostate cancer; who could get benefit from PARP inhibitors; how improve patients outcome with combinations strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Aberrations in the homologous recombination repair (HRR) pathway in prostate cancer (PCa) provide a unique opportunity to develop therapeutic strategies that take advantage of the reduced tumor ability to repair DNA damage. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have been shown to prolong the survival of PCa patients with HRR defects, particularly in those with Breast Cancer type 1 susceptibility protein/Breast Cancer type 2 susceptibility protein alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple preclinical and clinical studies are addressing potential synergies between PARPi and androgen receptor signaling inhibitors, and these strategies are also being evaluated in combination with other drugs such as immune checkpoint inhibitors. However, the effectiveness of these combining therapies could be hindered by multiple mechanisms of resistance, including also the role played by the immunosuppressive tumor microenvironment. In this review, we summarize the use of PARPi in PCa and the potential synergies with different molecular pathways. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi, expanding the use of genomic tests, and optimizing combination therapies., Competing Interests: VC has served as a consultant/advisory board member for Janssen, Astellas, Merck, AstraZeneca, Amgen, EISAI, Recordati, Novartis, and Bayer and has received speaker honoraria or travel support from Astellas, Janssen, Ipsen, Bayer, Gilead, and BristolMyers Squibb. No potential conflicts of interest were disclosed by the other authors., (© The Author(s), 2024.)

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging., Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination., Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy., Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters., Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases ( p  = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 ( p  = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant ( p  = 0.03) while a shorter PFS was associated with lung ( p  = 0.048) and brain metastases ( p  = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3., Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC., Competing Interests: V.C. has served as a consultant/advisory board member for Janssen, Astellas, Merck, AstraZeneca, Amgen, and Bayer and has received speaker honoraria or travel support from Astellas, Janssen, Ipsen, Bayer, and Sanofi. E.R. had a role as consultant for Bristol Meyers Squibb, MSD, Novartis, Pierre Fabre, Immunocore, and Pfizer., (© The Author(s), 2024.)

Background: Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC., Methods: A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) < 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC., Results: We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71-82)]. Median ADT duration in HSPC was 24 months (IQR = 14-40). Median follow-up was 91 months (IQR = 62-138), median OS and PFS from ARSI start were 20 (IQR 10-32) and 10 months (IQR = 5-19), respectively. In PP developing metastatic disease (n = 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54-2.64; LAD/ST: HR = 1.73; 95% CI 1.34-2.24; p < 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38-2.45; p < 0.001; LAD/ST: HR = 1.59; 95% CI 1.21-2.10; p < 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06-2.26; p = 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n = 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56-1.02, p = 0.064 and HR = 0.74, 95% CI 0.55-0.99, p = 0.042, respectively)., Conclusions: Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) genes in the Italian population is unknown., Objective: In this prospective multicenter cohort study, we evaluated the prevalence of gDDR alterations in the Italian population affected by metastatic prostate cancer (mPCa) and analyzed the impact on response to therapy, survival, and time to castration resistance., Design Setting and Participants: In an observational prospective trial, 300 consecutive Italian mPCa patients, enrolled in the Meet-Uro-10 trial from three academic Italian centers, were recruited between 2017 and 2019 and were screened for gDDR mutations in 107 genes., Outcome Measurements and Statistical Analysis: The primary endpoint was to assess the prevalence of gDDR mutations in the Italian population of patients with mPCa. The secondary endpoints included the association of gDDR subgroups with metastatic onset, Gleason score, and time to castration resistance., Results and Limitations: We identified 297 valuable patients. Forty-six patients had a pathogenic/likely pathogenic variant (15.5%, 95% confidence interval: 11.4-19.6): the more frequent was gBRCA2 found in nine cases (3%), followed by gATM in five cases (1.7%). In patients without mutations, longer median overall survival was observed with the sequence docetaxel-androgen receptor signaling inhibitor (ARSI) than with the sequence ARSI-docetaxel (87.9 vs 42 mo, p  = 0.0001). In a univariate analysis, the median time to castration resistance in gDDR mutated patients was 19.8 mo, versus 23.7 mo in no mutated patients ( p  = 0.024). There were no associations of gDDR subgroups with metastatic onset and Gleason score ≥8. In our cohort, variants of unknown significance in gDDR genes were found in 80 patients and might have a prognostic relevance., Conclusions: The study reported the prevalence of gDDR in the Italian population. The presence of gBRCA2 mutations correlates with a shorter time to the onset of castration resistance disease., Patient Summary: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to that in the Spanish population, identifying similarities between people of the Western Mediterranean area., (© 2024 The Authors.)

Background: PARP inhibitors (PARPis) are effective treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) as single agents or in combination with androgen receptor-targeted agents (ARTA). However, a clinically relevant adverse effect of these agents is hematological toxicity, a typical class adverse event (AE), which can lead to treatment modifications and discontinuations., Objective: We aimed to analyze the risk of hematological AEs, including anemia, neutropenia, and thrombocytopenia secondary to PARPi treatments in mCRPC., Patients and Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases, the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO) meeting abstracts for clinical trials concerning the use of PARPis, both as single agents and in combination, in patients with mCRPC. The search deadline was 30 June, 2023. We analyzed the pooled incidence of all grades of and ≥ G3 anemia, neutropenia, and thrombocytopenia. We subsequently calculated risk ratios (RRs) for all grades of and ≥ G3 AEs of PARPis versus non-PARPis from randomized clinical trials (RCTs)., Results: Eleven phase 2/3 trials with olaparib, niraparib, rucaparib, and talazoparib administered as single agents or combined with ARTA were selected. Anemia was the most common all grades (38.6%) and ≥ G3 AE (24.9%). In the analysis of relative risk, six RCTs were included. The administration of PARPis significantly increased the risk of developing all grades of anemia (RR = 2.44), neutropenia (RR = 3.15), and thrombocytopenia (RR = 4.66) compared with non-PARPis. Similarly, a significant increase in the risk of ≥ G3 anemia (RR = 5.73) and thrombocytopenia (RR = 5.44), and a not significant increased risk of neutropenia (RR = 3.41), were detected., Conclusions: In mCRPC, PARPis increase the risk of hematological toxicity compared with other treatments, both as single agents or combined with ARTA (high-quality evidence). Clinicians should be aware of this risk and the correct management, especially with the expected increased PARPis use in mCRPC., (© 2023. The Author(s).)

Despite remarkable progress in the last decade, metastatic prostate cancer (mPCa) remains incurable. The approval of PARP inhibitors (PARPis) represents a milestone in this field, which definitively enters the era of precision medicine, as mPCa is often enriched for defects of homologous recombination repair genes. PARPis are now used as single agents for patients with metastatic castration-resistant PCa. Moreover, combinations of PARPis plus androgen-receptor targeted agents and immune checkpoint inhibitors, and earlier applications of PARPis in the metastatic hormone-sensitive PCa are under evaluation, representing the possible upcoming applications of these agents. Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents., Competing Interests: Declaration of Competing Interest The authors did not declare any conflict of interest concerning the preparation of this manuscript entitled., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The main guidelines and recommendations for the implementation of the BRCA1/2 somatic test do not focus on the clinical application of predictive testing on bone metastases, a frequent condition in metastatic prostate cancer, by analyzing the critical issues encountered by laboratory practice. Our goal is to produce a document (protocol) deriving from a multidisciplinary team approach to obtain high quality nucleic acids from biopsy of bone metastases. This document aims to compose an operational check-list of three phases: the pre-analytical phase concerns tumor cellularity, tissue processing, sample preservation (blood/FFPE), fixation and staining, but above all the decalcification process, the most critical phase because of its key role in allowing the extraction of somatic DNA with a good yield and high quality. The analytical phase involves the preparation of the libraries that can be analyzed in various NGS genetic sequencing platforms and with various bioinformatics software for the interpretation of sequence variants. Finally, the post-analytical phase that allows to report the variants of the BRCA1/2 genes in a clear and usable way to the clinician who will use these data to manage cancer therapy with PARP Inhibitors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prostate cancer is the most commonly diagnosed cancer but the management of advanced prostate cancer remains a therapeutic challenge, despite the survival benefits imparted by several therapeutic discoveries targeting different molecular pathways. The mechanisms of resistance to androgen deprivation and tumour progression to lethal metastatic variants are often regulated by androgen receptor (AR) bypass mechanisms and/or neuroendocrine differentiation. Moreover, recent data also suggested the involvement of adaptive and innate infiltrated immune cells in prostate tumour progression. Improvements in cancer genome analyses contributed to a better understanding of antitumour immunity and provided solutions for targeting highly cancer-specific neoantigens generated from somatic mutations in individual patients. In this review, we investigated the current knowledge on the interplay between cancer development and the complex mechanisms of immune regulation. Particularly, we focused on the role of tumour immune microenvironment, generally characterised by strong barriers for immunotherapy, and we discuss the rationale for the potential application of single agent and combination immune-targeting strategies that could lead to improved outcomes. Careful selection based on clinical and genomic factors may allow identification of patients who could benefit from this treatment approach in multiple settings (from localised to advanced prostate tumour) and in different histological subtypes (from adenocarcinoma to neuroendocrine prostate cancer)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)