TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

Theranostics revolution in prostate cancer: Basics, clinical applications, open issues and future perspectives.

In the last years, theranostics has expanded the therapeutic options available for prostate cancer patients. In this review, we explore this dynamic field and its potential to revolutionize precision medicine for prostate cancer. We delve into the foundational principles, clinical applications, and emerging opportunities, emphasizing the potential synergy between radioligand therapy and other systemic treatments. Additionally, we address the ongoing challenges, including optimizing patient selection, assessing treatment responses, and determining the role of theranostics within the broader landscape of prostate cancer treatment.

Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab.

PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

Secreted miR-210-3p, miR-183-5p and miR-96-5p reduce sensitivity to docetaxel in prostate cancer cells.

Docetaxel (DCT) resistance is one of the main factors responsible for treatment failure in metastatic prostate cancer (PCa). Although several mechanisms of DCT resistance have been elucidated, the issue is still far from comprehensive. In this work we show that miR-96-5p, miR-183-5p and miR-210-3p (referred to as sDCTR-miRNAs) are specifically released by DCT resistant (DCTR) PCa clones and decrease the efficacy of DCT in PCa cells when overexpressed. Through bioinformatic analysis, we identified several potential targets of sDCTR-miRNAs' activity including FOXO1, IGFBP3, and PDCD4 known to exert a role in DCT resistance. Additionally, we found that PPP2CB and INSIG1 mediated the ability of sDCTR-miRNAs to reduce the efficacy of DCT. We explored whether secreted sDCTR-miRNAs could affect the phenotype of PCa cells. We found that exposure to exosomes derived from DCTR PCa clones (in which the content of sDCTR-miRNAs was higher than in exosomes from parental cells), as well as exposure to exosome loaded with sDCTR-miRNAs, reduced the cytotoxicity of DCT in PCa cells sensitive to the drug. Finally, we validated circulating miR-183-5p and miR-21-5p as potential predictive biomarkers of DCT resistance in PCa patients. Our study suggests a horizontal transfer mechanism mediated by exosomal miRNAs that contributes to reduce docetaxel sensitivity and highlights the relevance of cell-to-cell communication in drug resistance.

SIUrO best practice recommendations to optimize BRCA 1/2 gene testing from DNA extracted from bone biopsy in mCRPC patients (BRCA Optimal Bone Biopsy Procedure: BOP).

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.

[Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer]. / Terapia ormonale, assetto cardio-metabolico e cardiotossicità. Il lato ancora oscuro della cardioncologia ­ Parte 2: Tumore della prostata.

Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.

U-CHANGE Project: a multidimensional consensus on how clinicians, patients and caregivers may approach together the new urothelial cancer scenario.

Introduction: Advanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations ("as is" scenario) and recommend future actions ("to be" scenario). Methods: Twenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts. Results: Recommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies. Discussion: While the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the U-CHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

PURPOSE: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting. PATIENTS AND METHODS: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms. RESULTS: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). CONCLUSION: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

PURPOSE: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors. PATIENTS AND METHODS: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status. RESULTS: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). CONCLUSIONS: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.

Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer.

PURPOSE: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. EXPERIMENTAL DESIGN: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes. RESULTS: A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM. CONCLUSIONS: In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population.

Matching BRCA and prostate cancer in a public health system: Report of the Italian Society for Uro-Oncology (SIUrO) consensus project.

The recent approval of PARP inhibitors for the treatment of metastatic -castration-resistant prostate cancer (mCRPC) patients with BRCA mutations firstly introduced the possibility of proposing a targeted treatment in this disease. However, the availability of this therapeutic option raises a number of questions concerning the management of prostate cancer in everyday clinical practice: the timing and method of detecting BRCA mutations, the therapeutic implications of the detection, and the screening of the members of the family of a prostate cancer patient with a BRCA alteration. These challenging issues led the Italian Society for Uro-Oncology (SIUrO) to organise a Consensus Conference aimed to develop suggestions capable of supporting clinicians managing prostate cancer patients. The present paper described the development of the statements discussed during the consensus, which involved all of the most important Italian scientific societies engaged in the multi-disciplinary and multi-professional management of the disease.

nmCRPC, a look in the continuous care of prostate cancer patients: state of art and future perspectives.

Non-metastatic castration resistant prostate cancer (nmCRPC) is a clinical setting defined as confirmed rising levels of PSA in patients treated with ADT but without detectable metastases on conventional imaging with computerized tomography (CT) and technetium-99 m scintigraphy. Men with nmCRPC and a PSA doubling time (PSADT) ≤ 10 months are considered at high risk of rapidly developing metastases with a consequent possible impact on survival. Three recent phase III trials have demonstrated, in this setting, the efficacy of adding a next-generation androgen receptor targeted agent (ARTA) to ADT in respect to ADT only, in delaying the development of metastases (metastasis-free survival, MFS) and prolong overall survival. The magnitude of clinical benefit of these agents was even more meaningful if considering the low incidence of drug related adverse events. Our review described the latest advances in the management of nmCRPC, deriving from the pivotal clinical trials, SPARTAN, PROSPER and ARAMIS, in order to support clinicians to optimally manage these patients. Of note, the emergence of novel, more accurate, next-generation imaging techniques (including Ga PSMA-PET/CT), as well as eventual future tumor biomarkers, is modifying the entity and definition of the nmCRPC setting, with a consequent impact on patient's diagnosis and management.

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer.

PURPOSE: Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs). MATERIALS AND METHODS: In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased. RESULTS: 1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups. CONCLUSIONS: Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures.

STereotactic Ablative RadioTherapy in NEWly Diagnosed and Recurrent Locally Advanced Non-Small Cell Lung Cancer Patients Unfit for ConcurrEnt RAdio-Chemotherapy: Early Analysis of the START-NEW-ERA Non-Randomised Phase II Trial.

PURPOSE: This is a single arm phase 2 trial (Clinical trials.gov NCT05291780) to assess local control (LC) and safety of SAbR in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) unfit for concurrent chemo-radiation therapy (ChT-RT). METHODS: Neoadjuvant ChT was prescribed in fit patients. The tumor volume included primary tumor and any regionally positive node/s. The coprimary study endpoints were LC and safety. RESULTS: Between December 31, 2015, and December 31, 2020, 50 patients with LA-NSCLC were enrolled. Histology was squamous cell carcinoma and adenocarcinoma (ADC) in 52% and 48%, respectively. Forty (80%) patients had ultracentral tumor. Twenty-seven (54%) received neoadjuvant ChT and 7 (14%) adjuvant durvalumab. Median prescribed dose was 45 Gy (range, 35-55) and 40 Gy (35-45) in 5 daily fractions to tumor and node/s, respectively. After a median follow-up of 38 months (range, 12-80), 19 (38%) patients had experienced local recurrence (LR) at a median time of 13 months (range, 7-34). The median LR-free survival (FS) was not reached (95% confidence interval [CI], 28 to not reached). The 1-, 2-, and 3-year LR-FS rates were 86% ± 5%, 66% ± 7%, and 56% ± 8%, respectively. At last follow-up, 33 (66%) patients were alive. Median overall survival (OS) was 55 months (95% CI, 43-55 months). The 1-, 2-, and 3-year OS rates were 94% ± 3%, 79% ± 6%, and 72% ± 7%, respectively. No patients developed ≥ grade (G) 3 toxicity. ADC (hazard ratio [HR], 3.61; 95% CI, 1.15-11.35) was a significant predictor of better LC, while OS was significantly conditioned by smaller planning target volumes (HR, 1.004; 95% CI, 1.001-1.010) and tumor, node, and metastasis stage (HR, 4.8; 95% CI, 1.34-17). CONCLUSIONS: Patients with LA-NSCLC treated with SABR had optimal LC and promising OS in absence of ≥G3 toxicity. Our early outcomes would suggest the feasibility of using this approach in patients with LA-NSCLC unfit for concurrent ChT-RT.

Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study.

BACKGROUND: Although androgen deprivation therapy is typically given long-term for men with metastatic prostate cancer, second-generation hormone therapies are generally discontinued before the subsequent line of treatment. We aimed to evaluate the efficacy of continuing enzalutamide after progression in controlling metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel and prednisolone. METHODS: PRESIDE was a two-period, multinational, double-blind, randomised, placebo-controlled, phase 3b study done at 123 sites in Europe (in Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, Turkey, and the UK). Patients were eligible for period 1 (P1) of the study if they had histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, serum testosterone concentrations of 1·73 nmol/L or less, and had progressed during androgen deprivation therapy with a luteinising hormone-releasing hormone agonist or antagonist or after bilateral orchiectomy. In P1, patients received open-label enzalutamide 160 mg per day orally. At week 13, patients were assessed for either radiographic or prostate-specific antigen (PSA) progression (25% or more increase and 2 ng/mL or more above nadir). Patients who showed any decline in PSA at week 13 and subsequently progressed (radiographic progression, PSA progression, or both) were screened and enrolled in period 2 (P2), during which eligible patients were treated with up to ten cycles of intravenous docetaxel 75 mg/m2 every 3 weeks and oral prednisolone 10 mg/day, and randomly assigned (1:1) to oral enzalutamide 160 mg/day or oral placebo. Patients were stratified by type of disease progression. The block size was four and the overall number of blocks was 400. Patients, investigators, and study organisers were masked to treatment assignment. The primary endpoint was progression-free survival analysed in all patients in P2. This trial is registered with ClinicalTrials.gov, NCT02288247, and is no longer recruiting. FINDINGS: Between Dec 1, 2014, and Feb 15, 2016, 816 patients were screened for P1 of the study. 688 patients were enrolled in P1 and 687 received open-label enzalutamide. In P2, 271 patients were randomly assigned at 73 sites to receive enzalutamide (n=136) or placebo (n=135). The data cutoff for analysis was April 30, 2020. Median progression-free survival with enzalutamide was 9·5 months (95% CI 8·3-10·9) versus 8·3 months (6·3-8·7) with placebo (hazard ratio 0·72 [95% CI 0·53-0·96]; p=0·027). The most common grade 3 treatment-emergent adverse events were neutropenia (17 [13%] of 136 patients in the enzalutamide group vs 12 [9%] of 135 patients in the placebo group) and asthenia (ten [7%] vs six [4%]). The most common grade 4 treatment-emergent adverse event in P2 was neutropenia (23 [17%] of 136 patients in the enzalutamide group vs 28 [21%] of 135 patients in the placebo group). Serious treatment-emergent adverse events were reported in 67 (49%) of 136 patients in the enzalutamide group and 52 (39%) of 135 patients in the placebo group. Two (15%) of 13 deaths in the enzalutamide group (caused by septic shock and haematuria) and one (14%) of seven deaths in the placebo group (caused by actue kidney injury) were associated with docetaxel. INTERPRETATION: PRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone. FUNDING: Astellas Pharma and Pfizer.

Targeted Approaches in Metastatic Castration-Resistant Prostate Cancer: Which Data?

Prostate cancer is the second most common diagnosed cancer and the fifth leading cause of cancer-related deaths in men worldwide. Despite significant advances in the management of castration-sensitive prostate cancer, the majority of patients develop a castration-resistant disease after a median duration of treatment of 18-48 months. The transition to a castrate resistance state could rely on alternative survival pathways, some related to androgen-independent mechanisms. Although several agents have been approved in this setting, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Recent studies revealed some of the complex pathways underlying inherited and acquired mechanisms of resistance to available treatments. A better understanding of these pathways may lead to significant improvements in survival by providing innovative therapeutic targets. The present comprehensive review attempts to provide an overview of recent progress in novel targeted therapies and near-future directions.

The amount of DNA combined with TP53 mutations in liquid biopsy is associated with clinical outcome of renal cancer patients treated with immunotherapy and VEGFR-TKIs.

BACKGROUND: Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC). METHODS: Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings. RESULTS: A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/µl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004). CONCLUSIONS: The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.

Perspectives in Immunotherapy: meeting report from the Immunotherapy Bridge, December 1st-2nd, 2021.

Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues. PATIENTS AND METHODS: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes. RESULTS: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001). CONCLUSION: Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.