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In this article, we report the breakthrough acquisitions for renal cell carcinoma (RCC) management presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. The results from Keynote 564 showed an impressive overall survival (OS) advantage for pembrolizumab, in patients at higher risk of relapse after surgery and confirmed the benefit in terms of disease-free survival (DFS). Until now, pembrolizumab is the only immune checkpoint inhibitor (ICI) to prove a survival advantage. On the contrary, the results from CheckMate 914 trial showed the lack of benefit of adjuvant nivolumab. In the metastatic setting, the longer-term follow-up data of the CheckMate 9ER and CheckMate 214 trials reassessed the undoubtable role of ICI-based combination in first-line treatment, with a clear survival advantage in the subgroup of patients at intermediate/poor IMDC prognosis. No OS advantage was seen in favorable IMDC risk group patients. This 2024 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized therapy for RCC patients.

The 2024 ASCO Genitourinary Cancer Symposium, this year celebrating the 20th anniversary, delved into key advancements in urothelial carcinoma (UC) and prostate cancer (PC). For UC, insights emerged from adjuvant pembrolizumab for muscle-invasive urothelial carcinoma, and from the efficacy of the EV-302 study of enfortumab vedotin +pembrolizumab in the metastatic setting. In PC, adjuvant therapy with high-dose radiotherapy schedules plus long-t erm ADT was explored. In metastatic castration-resistant PC, highlights included a novel combo (cabozantinib+atezolizumab) for poor prognosis patients; confirmed benefits of ARSI+PARPi in BRCA-mutated patients; and safety considerations for ARSI treatments. The symposium continued its role as an indispensable platform for shaping specialized oncological care.

Introduction: Combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) can be responsible for major adverse cardiovascular events (MACEs). We performed a meta-analysis to assess the relative risk (RR) of MACEs and hypertension in cancer patients treated with ICI+TKI combinations., Research Design and Methods: We selected prospective trials through MEDLINE/PubMed, Cochrane Library, and ASCOMeeting abstracts. We calculated combined ORs, RRs, and 95% CIs using RevMansoftware for meta-analysis (v.5.2.3)., Results: Seven studies were selected for the analysis of MACEs (3849 patients). The incidence MACEs were 0.8% with ICI+TKI combinations, compared to 0.2% in the control arms for both any- and high-grade. ICI+TKI combinations significantly increased the risk of any- (OR = 3.21; p  = 0.01) and high-grade MACEs (OR = 2.72; p  = 0.05). Ten studies were selected for the analysis of hypertension (5744 patients). The incidence of treatment-related hypertension of any-grade and high-grade was41.3% (vs. 20.8%) and 26.1% (vs. 12.3%) with ICI+TKI combinations, respectively. ICI+TKI combinations significantly increased the risk of treatment-related hypertension of any-grade (RR = 2.10; p  = 0.001), but not of high-grade ( p  = 0.11)., Conclusions: ICI+TKI combinations increase the risk of MACEs compared to controls, although the absolute incidence is eventually low. Routine cardiovascular monitoring in asymptomatic patients is therefore not recommended.

This article describes the main acquisitions of renal cell carcinoma (RCC) management presented during the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. In particular, the efficacy of adjuvant pembrolizumab in patients with resected renal cell carcinoma (RCC) at increased risk of recurrence was confirmed through a subgroup analysis. In the metastatic setting, the updated analysis of the CheckMate 9ER study confirmed the efficacy in terms of overall survival (OS) of the combination of nivolumab plus cabozantinib; of note, this survival advantage was clear in the subgroup of patients at poor IMDC prognosis, but not in favorable IMDC risk group patients. As concern the triplet therapy (i.e. nivolumab+ipilumumab+cabozantinib), the updated analysis of the COSMIC-313 study confirmed a significant PFS advantage in the subgroup of mRCC patients at intermediate IMDC risk, while the lack of benefit in the poor risk group supports the critical role of immunotherapy (but not of VEGFR-TKIs) in this poor prognosis subgroup of patients. Finally, the activity of cabozantinib as second-line therapy after progression to ICI-based combinations was prospectively assessed. This 2023 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.

In this article, we describe the main acquisitions of urothelial carcinoma (UC) management reported at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium. A major development of this year was characterized by the confirmation of a disease-free survival advantage of adjuvant nivolumab for high-risk muscle-invasive urothelial carcinoma after radical resection at longer follow-up. In the metastatic setting, the updated analysis of the IMvigor130 study confirmed the failure of the strategy of adding immunotherapy (i.e. atezolizumab) to first-line chemotherapy; analogously atezolizumab monotherapy did not improve overall survival compared to chemotherapy in untreated metastatic urothelial carcinoma (mUC). Furthermore, interesting data were presented concerning future treatment options. In particular, immunotherapy (IO) with pembrolizumab showed promising activity in patients with high-risk non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin (KEYNOTE-057). The antibody-drug conjugate sacituzumab govitecan demonstrated a relevant activity in platinum (PT)-ineligible mUC patients progressed after prior IO. Certainly, the lack of predictive biomarkers of response to a specific therapy highlights the urgent need for comprehensive characterization of UC for a personalized therapeutic approach that will improve patient outcomes.

Background: Prostate cancer (PC) is a heterogeneous disease that requires a personalized treatment approach for proper patient management., Aim: We analyzed a selected overview of the most important news recently presented at the 2021 ASCO genitourinary cancer symposium., Results: In particular, we focused on the identification of predictive biomarkers as potential targets for therapy. Molecular signatures of increased T cell activity, proliferation, and hormone dependence were associated with greater probability of response to apalutamide in non-metastatic CRPC. Pathogenic variants of DDR genes mutations detected with circulating tumor DNA (ctDNA) analysis, which had a high concordance with tumor tissue analysis, might represent a useful way for selecting mutated patients for poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors therapy. Loss of PTEN could be a target for ipatasertib (a pan-AKT inhibitor) associated with abiraterone in mCRPC patients., Conclusions: The 2021 ASCO Genitourinary Cancers Symposium significantly contributed to the complex research goal of intimately understanding PC carcinogenesis with the ultimate aim of improving patient outcomes.

Background: The 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium represents an unmissable event for oncologists who deal with renal cell carcinoma (RCC)., Aim and Results: This article describes the main acquisitions of RCC management, including the advent of a new combo (pembrolizumab+lenvatinib) as first-line therapy, the confirmation of an OS advantage of ICI plus VEGFR-TKI combinations over sunitinib at longer follow-up, the persistent benefit from these combinations in particular subgroups (clear cell mRCC tumors with sarcomatoid differentiation), and possible new approaches in subsequent lines of therapy (including the HIF-2α inhibitor belzutifan)., Conclusions: This 2021 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.

Introduction: Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib., Areas Covered: We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects. Preclinical investigations of cabozantinib in combination with other anticancer drugs are also reviewed., Expert Opinion: Preclinical evidence shows that cabozantinib has antitumor activity against various cancer cells and exhibits synergy with other anticancer agents, including immune checkpoint inhibitors and hormone receptor or metabolic pathway inhibitors. Further optimization of cabozantinib treatment requires the identification of biomarkers of response and resistance, and exploration of complementary drug targets. Investigation of mechanisms of adaptive resistance, such as epithelial to mesenchymal transition (cancer intrinsic) and immunomodulation by the tumor microenvironment (cancer extrinsic), as well as identification of novel drug targets based on characterization of cancer stem cell metabolomic phenotypes, appear to be promising approaches.

Introduction : Prostate cancer (PCa) is one of the most common adult malignancies worldwide, and a major leading cause of cancer-related death in men in Western societies. In the last years, the prognosis of advanced PCa patients has been impressively improved thanks to the development of different therapeutic agents, including taxanes (docetaxel and cabazitaxel), second-generation anti-hormonal agents (abiraterone and enzalutamide), and the radiopharmaceutical Radium-223. However, great efforts are still needed to properly select the most appropriate treatment for each single patient. Areas covered : Several prognostic or predictive biomarkers have been studied, none of which has an established validated role in daily clinical practice. This paper analyzed the major biomarkers (including PSA, androgen receptor (AR) splice variants, βIII-tubulin, ALP, circulating tumor cells, and DNA repair genes) with a potential prognostic and/or predictive role in advanced PCa patients. Expert commentary : Surrogate biomarkers - measurable, reproducible, closely associated with tumor behavior and linked to relevant clinical outcomes - are urgently needed to improve PCa patient management.

Objective : Hypertension is a common adverse event with targeted agents in cancer patients and can lead to serious and sometimes lethal cardiovascular complications. The authors performed a meta-analysis of clinical trials aiming to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade Hypertension Events (HE) in patients with solid tumors receiving targeted therapy. Methods : A review of citations from PubMed was performed and studies were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search was limited to randomized phase III trials published in English focused on the efficacy and safety of targeted agents in cancer patients, reporting data on HE. Incidence, RR and relative 95% CIs were analyzed using random or fixed-effects models. Overall incidences were calculated and further compared with the chi-squared test for proportions. Results : Ninety-three phase III trials were included, with a total of 68,077 patients. Prostate cancer was the most represented (18.9%), followed by breast cancer (17.3%) and colorectal cancer (16.4%). The incidence of all- and high-grade HE was 23.47% and 8.57%, respectively, with the highest incidence of serious HE reported by adjuvant Sunitib/Sorafenib (29.03%). The highest RR of high-grade HE was observed with Bevacizumab in patients with advanced cervical cancer. By drug category, the highest RR of high-grade HE was reported by VEGFR/EGFR TKIs. Conclusion : According to these data, monitoring this class of toxicities is of primary importance to avoid hypertension worsening and, thus, the risk of major cardiovascular events.

Introduction: Over the last decade, epidermal growth factor receptor (EGFR) signaling was investigated as a potential target for tyrosine kinase inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Necitumumab is a fully humanized IgG1 monoclonal antibody directed against the binding domain of EGFR, approved in combination with cisplatin-gemcitabine for the first-line treatment of squamous NSCLC. Areas covered: The purpose of this manuscript is to systematically review the state of the art of necitumumab for the treatment of metastatic NSCLC, focusing on predictive factors, cost-effectiveness, and future potential combinations with additional agents. Expert opinion: Despite recent therapeutic advances, platinum-based chemotherapy still represents the most widely used first-line treatment for advanced NSCLC, particularly for the squamous histotype. Necitumumab is nowadays the first targeted agent providing an (statistically significant) additional survival gain to squamous NSCLC patients when combined with first-line chemotherapy at the cost of an increased (although manageable) toxicity, as shown in the SQUIRE trial. Hopefully, improvement in patients' selection by identifying reliable predictive markers and the combination with new agents may help to maximize the benefit of this targeted treatment, which is currently limited by a not optimal cost-benefit ratio.

Introduction: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents.

Introduction: Since both cytotoxic and cytokine therapy were not able to improve the prognosis of advanced renal cell carcinoma (RCC), this tumor has been a good model for the development of new biological agents in the past decade. Five VEGF receptor (VEGFR) and two mammalian target of rapamycin (mTOR) inhibitors are currently available for treatment of this disease but several issues need to be resolved such as a better definition of prognosis, the overcome of resistance and the best therapy for less frequent histologies., Areas Covered: This review focuses on new tyrosine kinase inhibitors (TKIs) under investigation in these patients. Study design, phase of investigation, result and emerging toxicities were reported for each molecule. Combination trials involving TKIs with other strategies such as immunotherapy were also covered., Expert Opinion: Despite the development of more potent and more specific VEGFR TKIs, all tumors ultimately develop resistance to therapy and a plateau has been reached in terms of overall survival. Current research effort to develop new agents aims at overcoming both the primary and the acquired resistance to anti-VEGFR TKIs focusing on new molecular pathways. The ultimate goal is not only to improve patient outcome but to achieve durable complete remission. Several pitfalls that have been responsible for failure of other compounds remain, especially the lack of strong predictive biomarkers and the use of inappropriate tumor assessment criteria that may not accurately capture response to these new therapies.

Tyrosine kinase inhibitors are de facto the most commonly used targeted therapies for upfront treatment of metastatic renal cell carcinoma (mRCC). After the first era in which targeted agents were compared with placebo and interferon-α, a new phase has started in recent years characterized by head-to-head trials comparing targeted agents in superiority or non-inferiority trials. Recently, the results a head-to-head phase III trial comparing axitinib to sorafenib as upfront therapy in patients affected by mRCC have been reported. We discuss several critical aspects of this study and the results of our metaanalysis on the activity of axitinib over sorafenib in a larger population with the intent to confirm the superiority of axitinib. Despite this, the definition of primary endpoint remains a central factor in determining the final results of a trial.

Tyrosine kinase inhibitors are de facto the more used targeted therapies for upfront treatment of metastatic renal cell carcinoma (mRCC). Among these, sunitinib and pazopanib have reported greater activity in term of progression-free survival and overall survival compared with interferon-α or placebo in two independent large phase III studies. Despite a large use in clinical practice these molecules had never been compared. The COMPARZ study recently published in the New England Journal of Medicine reports the results of a non-inferiority trial that comparing pazopanib to sunitinib as first line of therapy in mRCC patients. Here we report the activity and safety data of the study and we discuss several critical aspects related to the study design and possible confounding factors that may alter the results' interpretation.

Current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Cabazitaxel, a new taxane with potential antineoplastic activity, has been approved by Food and Drug Administration (FDA) after docetaxel failure. In a phase III trial, cabazitaxel showed increased overall survival (OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Furthermore, chemotherapy is not the only strategy available: several studies have shown as CRPC remains dependent on androgen receptor function for growth. Abiraterone acetate, an irreversible inhibitor of CYP17, has also been approved by FDA after docetaxel failure. In a phase III trial comparing abiraterone acetate to placebo, abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR 0.65, 95% CI 0.54-0.77; p < 0.0001). This review will discuss current options and the ongoing trials for second-line treatment of CRPC including chemotherapy, hormonal therapies, antiangiogenetic and immune strategies.

Targeted therapies have improved survival in patients with metastatic renal cell cancer (RCC); however, expert opinion on the optimal therapeutic strategy is divided. This retrospective study evaluates different sequential schemes of targeted therapies in 310 patients with advanced/metastatic RCC who received different systemic agents - sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and axitinib - alone or in different sequences, until disease progression or intolerable toxicity (median follow-up: 37 months). The median overall survival (OS) was 22 months and the 5-year OS was 23.4%; differential therapeutic schemes were not associated with differences in OS. A worse performance status, no nephrectomy and a poor-risk classification according to the Motzer criteria was associated with a shorter OS. These findings support the use of targeted therapies in the treatment of RCC, even in a large unselected population from a single institution, and suggest that treatment should be tailored to meet individual circumstances and needs.