Development and validation of a new tool to estimate early mortality in patients with advanced cancer treated with immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored. METHODS: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort. RESULTS: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71-0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64-0.80). CONCLUSION: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression.

Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4.

The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2'-methylenebis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl)ethane, and 2,2'-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and 'DNA-templated DNA replication' which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.

Hypertransaminasemia in cancer patients receiving immunotherapy and immune-based combinations: the MOUSEION-05 study.

BACKGROUND: The antitumor efficacy of immune checkpoint inhibitors (ICIs) has increasingly emerged during the last few years. However, there is a need to identify the safety profile of these agents more comprehensively, including liver toxicity. MATERIALS AND METHODS: Herein, we performed a meta-analysis to assess the risk of all-grade and grade 3-4 hypertransaminasemia in cancer patients receiving ICIs-as monotherapy or in combination with other anticancer agents. All the relevant trials were retrieved through EMBASE, Cochrane Library, and PubMed/Medline databases; eligible studies were selected according to PRISMA statement. The pooled relative risk (RR) and 95% confidence interval (CI) were extracted. RESULTS: Fifty-nine studies were included. The pooled RRs for all-grade AST and ALT increase were 1.45 (95% CI 1.26-1.67) (Supplementary Fig. 3) and 1.51 (95% CI 1.29-1.77) in patients receiving ICIs monotherapy and immune-based combinations compared to control treatment, respectively. The pooled RRs for grade 3-4 AST and ALT increase were 2.16 (95% CI 1.77-2.64) and 2.3 (95% CI 1.91-2.77). CONCLUSIONS: According to our results, ICIs monotherapy and immune-based combinations were associated with higher risk of all-grade and grade 3-4 hypertransaminasemia. Monitoring liver function should be recommended in cancer patients treated with ICIs monotherapy or immune-based combination, and in case of underlying liver disease, a careful risk-benefit assessment appears as a mandatory need.

Complete remissions following immunotherapy or immuno-oncology combinations in cancer patients: the MOUSEION-03 meta-analysis.

BACKGROUND: Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients. METHODS: The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted. RESULTS: A total of 12,130 potentially relevant trials were identified; 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n = 14,249; 29%), urothelial cancer (n = 6536; 13%), renal cell carcinoma (n = 5743; 12%), and melanoma (n = 2904; 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90). CONCLUSIONS: To the best of the authors' knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments.

Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro.

Plastic in oceans degrades to microplastics and nanoplastics, causing various problems for marine fauna and flora. Recently, microplastic has been detected in blood, breast milk and placenta, underlining their ability to enter the human body with still unknown effects. In addition, plastic contains other compounds such as plasticizers, antioxidants or lubricants, whose impact on human health is also elusive. On the cellular level, two transporters involved in cell protection and detoxification of xenobiotic compounds are the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Despite the great importance of these proteins to maintain the correct cellular balance, their interaction with plastic and related products is evasive. In this study, the possible interaction between different plastic-related compounds and these two transporters was investigated. Applying virtual compound screening and molecular docking of more than 1000 commercially available plastic compounds, we identified candidates most probably interacting with these two transporters. Cytotoxicity and uptake assays confirmed their toxic interaction on P-glycoprotein-overexpressing CEM/ADR5000 and BCRP-overexpressing MDA-MD-231-BCRP cell lines. To specifically visualize the results obtained on the P-glycoprotein inhibitor 2,2'-methylenebis(6-tert-butyl-4-methylphenol), we performed live cell time-lapse microscopy. Confocal fluorescence microscopy was used to understand the behavior of the molecule and the consequences that it has on the uptake of the well-known substrate doxorubicin and, in comparison, with the known inhibitor verapamil. Based on the results, we provide evidence that the compound in question is an inhibitor of the P-glycoprotein. Moreover, it is also possible that 2,2'-methylenebis(6-tert-butyl-4-methylphenol), together with three other compounds, may also inhibit the breast cancer resistance protein. This discovery implies that plastic-related compounds can not only harm the human body but can also inhibit detoxifying efflux pumps, which increases their toxic potential as these transporters lose their physiological functions.

The Effect of Plastic-Related Compounds on Transcriptome-Wide Gene Expression on CYP2C19-Overexpressing HepG2 Cells.

In recent years, plastic and especially microplastic in the oceans have caused huge problems to marine flora and fauna. Recently, such particles have also been detected in blood, breast milk, and placenta, underlining their ability to enter the human body, presumably via the food chain and other yet-unknown mechanisms. In addition, plastic contains plasticizers, antioxidants, or lubricants, whose impact on human health is also under investigation. At the cellular level, the most important enzymes involved in the metabolism of xenobiotic compounds are the cytochrome P450 monooxygenases (CYPs). Despite their extensive characterization in the maintenance of cellular balance, their interactions with plastic and related products are unexplored. In this study, the possible interactions between several plastic-related compounds and one of the most important cytochromes, CYP2C19, were analyzed. By applying virtual compound screening and molecular docking to more than 1000 commercially available plastic-related compounds, we identified candidates that are likely to interact with this protein. A growth inhibition assay confirmed their cytotoxic activity on a CYP2C19-transfected hepatic cell line. Subsequently, we studied the effect of the selected compounds on the transcriptome-wide gene expression level by conducting RNA sequencing. Three candidate molecules were identified, i.e., 2,2'-methylene bis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl) ethane, and 2,2'-methylene bis(6-cyclohexyl-4-methylphenol)), which bound with a high affinity to CYP2C19 in silico. They exerted a profound cytotoxicity in vitro and interacted with several metabolic pathways, of which the 'cholesterol biosynthesis process' was the most affected. In addition, other affected pathways involved mitosis, DNA replication, and inflammation, suggesting an increase in hepatotoxicity. These results indicate that plastic-related compounds could damage the liver by affecting several molecular pathways.

Risk of toxicity with immunotherapy-tyrosine kinase inhibitors for metastatic renal cell carcinoma: a meta-analysis of randomized controlled trials.

Aim: Few data are available regarding the safety profile of immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations in metastatic renal cell carcinoma. The authors investigated all-grade and grade 3-4 (G3-4) adverse events in trials comparing IO-TKI combinations with sunitinib monotherapy. Methods: The relative risks of several all-grade and G3-4 adverse events were analyzed. Results: Relative risks were similar between patients receiving IO-TKI combinations versus sunitinib monotherapy. However, the use of IO-TKI combinations was associated with a higher risk of all-grade and G3-4 diarrhea, all-grade hypothyroidism, G3-4 decreased appetite, all-grade and G3-4 aspartate transaminase increase and all-grade and G3-4 alanine transaminase increase. Conclusion: The results of the authors' meta-analysis suggest that risks of treatment-related adverse events should be carefully considered when choosing IO-TKI combinations in metastatic renal cell carcinoma patients.

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What's the Story Morning Glory?

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.

An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT.

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes' alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.

Treating Prostate Cancer by Antibody-Drug Conjugates.

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called "antibody-drug conjugates" (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells' surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis.

Pyrrolizidine alkaloids (PAs) are one of the largest distributed classes of toxins in nature. They have a wide range of toxicity, such as hepatotoxicity, pulmonary toxicity, neuronal toxicity, and carcinogenesis. Yet, biological targets responsible for these effects are not well addressed. Using methods of computational biology for target identification, we tested more than 200 PAs. We used a machine-learning approach that applies structural similarity for target identification, ChemMapper, and SwissTargetPrediction. The predicted target with high probability was muscarinic acetylcholine receptor M1. The predicted interactions between this target and PAs were further studied by molecular docking-based binding energies using AutoDock and VinaLC, which revealed good binding affinities. The PAs are bound to the same binding pocket as pirenzepine, a known M1 antagonist. These results were confirmed by in vitro assays showing that PAs increased the levels of intracellular calcium. We conclude that PAs are potential acetylcholine receptor M1 antagonists. This elucidates for the first time the serious neuro-oncological toxicities exerted by PA consumption.

How Do Molecular Classifications Affect the Neoadjuvant Treatment of Muscle-Invasive Urothelial Carcinoma?

Despite the significant improvements in the field of oncological treatments in recent decades, and the advent of targeted therapies and immunotherapy, urothelial carcinoma of the bladder remains a highly heterogeneous and difficult-to-treat neoplasm with a poor prognosis. In this context, owing to the new methods of genomic sequencing, numerous studies have analyzed the genetic features of muscle-invasive bladder cancer, providing a consensus set of molecular classes, to identify malignancies that may respond better to specific treatments (standard chemotherapy, immunotherapy, target therapy, local-regional treatment, or combinations) and improve the survival. The aim of the current review is to provide an overview of the current status of the molecular landscape of muscle-invasive bladder cancer, focusing our attention on therapeutic and prognostic implications in order to select the most effective and tailored therapeutic regimen for the individual patient.

Novel Immune Checkpoint Inhibitor Targets in Advanced or Metastatic Renal Cell Carcinoma: State of the Art and Future Perspectives.

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway.

Chromosome 3p gene alterations as biomarkers for immunocombinations in metastatic renal cell carcinoma: A hypothesis-generating analysis.

BACKGROUND: Identifying biomarkers for metastatic renal cell carcinoma (mRCC) is an unmet need in actual immunotherapy era. Available data regarding chromosome 3p genes (i.e., VHL, PBRM1, SETD2) mutations as potential predictors for therapy response is conflicting. We describe the impact of these mutations on clinical outcomes in mRCC patients treated with immune checkpoint inhibitor (ICI)-doublet or ICI/tyrosine kinase inhibitor (TKI) combinations. METHODS: We performed a single-center retrospective analysis on mRCC patients treated with first line ICI/ICI or ICI/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93 kb, human reference sequence hg19/GRCh37) in the coding sequences of the following genes: ATM, BAP1, KDM5C, MET, MTOR, NF2, PBRM1, PIK3CA, PTEN, SETD2, SMARCB1, TP53, TSC1, TSC2, VHL. RESULTS: 18 patients undergoing ICI/ICI and ICI/TKI who had tumor tissue adequate for molecular analysis were included. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% ICI/TKI, 11% ICI/ICI. 83.3% pts (n = 15) carried genomic alterations (GA). Most common GA included VHL in 44% (n = 8; 7 pathogenic - PAT and 1 variant of unknown significance - VUS), PBRM1 in 44% (n = 8; 5 PAT and 3 VUS) and SETD2 in 33% (n = 6; 4 PAT and 2 VUS). With the limit of a small sample that did not allow proper statistical analyses, SETD2-mutated patients had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated patients. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1 +VHL mutated pts. CONCLUSIONS: Our data shows a possible negative predictive role of SETD2 GA for ICI-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for ICI/TKI efficacy. Our hypothesis-generating analysis highlights the need of an integrated evaluation of these genes as promising biomarkers in RCC. Further larger studies are required.

TERT promoter mutations and the outcome of patients with advanced urothelial carcinoma treated by platinum-based chemotherapy or pembrolizumab.

BACKGROUND: TERT promoter mutation is one of the most common genomic alterations in urothelial carcinoma (UC). Its prognostic role on patients' outcomes is still not clear. METHODS: We performed a single-center retrospective analysis on patients with advanced UC treated with platinum-based chemotherapy or immunotherapy to assess the presence of somatic TERT-124[C>T] and TERT-146[C>T] mutations and their association with clinicopathologic factors and survival outcomes. Patients were assessed for Overall Survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR). RESULTS: We analyzed 45 UC tumors; 38 of them received first-line chemotherapy and 21 second-line pembrolizumab; 6 patients (13%) harbored -146 C > T TERTp mutation and 25 patients (56%)-124 C > T. The presence of TERT promoter mutations was associated with a higher rate of lower tract UC and a lower rate of synchronous or lymph node metastases. TERT wild-type patients showed higher 12- and 24-months OS-rates in the chemotherapy subgroup and 6-, 12- and 24-months OS rates in the pembrolizumab subgroup. The presence of TERT promoter mutations was also associated with a lower 6 months-PFS rate in patients receiving chemotherapy and in all the three time points in those treated by pembrolizumab. The ORRs of pembrolizumab were 21% and 71% in patients with or without TERT promoter mutations, respectively (p < 0.001). CONCLUSIONS: Our analysis suggests that the presence of TERT promoter mutations could negatively affect the outcome of UC patients treated by chemotherapy or pembrolizumab. This hypothesis should be further evaluated in wider cohorts.

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

Prognostic and predictive biomarkers for immunotherapy in advanced renal cell carcinoma.

The therapeutic algorithm of renal cell carcinoma has been revolutionized by the approval of immunotherapy agents by regulatory agencies. However, objective and durable responses are still not observed in a large number of patients, and prognostic and predictive biomarkers for immunotherapy response are urgently needed. Prognostic models used in clinical practice are based on clinical and laboratory factors (such as hypercalcaemia, neutrophil count or Karnofsky Performance Status), but, with progress in molecular biology and genome sequencing techniques, new renal cell carcinoma molecular features that might improve disease course and outcomes prediction have been highlighted. An implementation of current models is needed to improve the accuracy of prognosis in the immuno-oncology era. Moreover, several potential biomarkers are currently under evaluation, but effective markers to select patients who might benefit from immunotherapy and to guide therapeutic strategies are still far from validation.

Prostate cancer and novel pharmacological treatment options-what's new for 2022?

INTRODUCTION: Androgen deprivation therapy (ADT) plus Androgen Receptor Target Agents (ARTAs) or docetaxel are the actual standard of care in prostate cancer (PC). Several therapeutic options are available for pretreated patients: cabazitaxel, olaparib, and rucaparib for BRCA mutations, Radium-223 for selected patients with symptomatic bone metastasis, sipuleucel T, and 177 LuPSMA-617. AREAS COVERED: This review the new potential therapeutic approaches and the most impacting recent published trials to provide an overview on the future management of PC. EXPERT OPINION: Currently, there is a growing interest in the potential role of triplet therapies encompassing ADT, chemotherapy, and ARTAs. These strategies, explored in different settings, appeared to be particularly promising in metastatic hormone-sensitive PC. Recent trials investigating ARTAs plus poly(adenosine diphosphate-ribose) polymerase (PARPi) inhibitor provided helpful insights for patients with metastatic castration resistant disease, regardless of homologous recombination genes status. Otherwise, the publication of the complete data is awaited, and more evidence is required. In advanced settings, several combination approaches are under investigation, to date with contradictory results, such as immunotherapy plus PARPi or chemotherapy. The radionuclide 177Lu-PSMA-617 proved successful outcomes in pretreated mCRPC patients. Additional studies will better clarify the appropriate candidates to each strategy and the correct treatments' sequence.

An update on safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma.

INTRODUCTION: Significant advances have been made in the first-line therapy of metastatic renal cell carcinoma (mRCC) since the approval of immune-based combinations, including nivolumab plus ipilimumab or cabozantinib, and pembrolizumab plus axitinib or lenvatinib. AREAS COVERED: The aim of this review is to compare the different safety profiles of first-line immune-based combinations versus sunitinib across the four respective pivotal trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR), with a particular attention to patients' health-related quality of life (HRQoL) assessment. EXPERT OPINION: The concurrent use of an immune-checkpoint inhibitor (ICI) with a tyrosine kinase inhibitor (TKI) as a first-line treatment strategy for mRCC has highlighted the unmet clinical need for prompt detection and consequently proper management of adverse events (AEs), both immune-related and TKI-induced. Overlapping AEs, such as hypertransaminasemia, are most challenging to manage, and evidence is still outlined from clinical practice. The specific patterns of toxicities of the approved first-line immune-based combinations, along with the impact of these interventions on patients' HRQoL, demand a deeper consideration by physicians while choosing the appropriate treatment for each individual mRCC patient. Both safety profile and HRQoL evaluation could be exploited to guide the first-line treatment selection in this setting.