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Purpose of ReviewNeuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype of prostate cancer that most commonly arises in later stages of prostate cancer as a mechanism of treatment resistance. The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents. Here, we review the clinical and molecular features of NEPC based on recent studies and outline future strategies and directions.Recent FindingsNEPC can arise “de novo” but most commonly develops as a result of lineage plasticity whereby prostate cancer cells adopt alternative lineage programs as a means to bypass therapy. Dependence on androgen receptor (AR) signaling is lost as tumors progress from a prostate adenocarcinoma to a NEPC histology, typically manifested by the downregulation of AR, PSA, and PSMA expression in tumors. Genomic analyses from patient biopsies combined with preclinical modeling have pointed to loss of tumor suppressors RB1 and TP53 as key facilitators of lineage plasticity. Activation of oncogenic drivers combined with significant epigenetic changes (e.g., EZH2 overexpression, DNA methylation) further drives tumor proliferation and expression of downstream neuronal and neuroendocrine lineage pathways controlled in part by pioneer and lineage determinant transcription factors (e.g., SOX2, ASCL1, BRN2). These biologic insights have provided a framework for the study of this subgroup of advanced prostate cancers and have started to provide rationale for the development of biomarker-driven therapeutic strategies.SummaryFurther study of the dynamic process that leads to NEPC is required for the development of effective strategies to identify and treat patients developing lineage plasticity as a mechanism of treatment resistance.

Purpose of ReviewThe treatment options for high-risk non-muscle invasive bladder cancer (NMIBC), particularly following BCG, remain limited. We highlight recent, promising therapies for high-risk NMIBC.Recent FindingsSeveral therapies utilizing different mechanisms of action have demonstrated favorable results in the BCG-naïve and BCG-unresponsive settings. These treatments include intravenous and intravesical immunotherapy, viral- and bacterial-based intravesical therapies, combination intravesical chemotherapy regimens, and novel intravesical chemotherapy administration. Overall, the efficacy and tolerability of emerging treatments for NMIBC appear promising and provide potential alternatives to radical cystectomy.SummaryAs the landscape of managing BCG-unresponsive disease evolves, clinical trials will explore future options and determine effective alternatives.

Purpose of ReviewRecent whole genome characterizations of primary human bladder cancers revealed that they can be grouped into “intrinsic” basal and luminal molecular subtypes. Here, we provide an overview of the subtypes and discuss their biological and clinical properties.Recent FindingsBasal cancers are characterized by advanced stage and metastatic disease at presentation. They tend to be enriched with squamous and small cell/neuroendocrine features and inactivating mutations and deletions of TP53 and RB1. Basal cancers can be divided into “epithelial” and “mesenchymal” (also known as “claudin low”) subsets, and a portion of the latter form a “neuroendocrine/neuronal” subset that is associated with particularly poor survival. Luminal cancers are often enriched with papillary histopathological features and activating mutations in FGFR3, and they can also be divided into additional subsets based on differential stromal cell infiltration, relative genomic instability, and high- versus low-level expression of carcinoma in situ (CIS) gene expression signatures. Importantly, the bladder cancer molecular subtypes display differential sensitivities to neoadjuvant chemotherapy and immune checkpoint blockade, and preliminary data also suggest that they respond differently to radiation with or without hypoxia modulation. Ongoing studies are investigating the relevance of the molecular subtypes to the bladder cancer histopathological variants and to upper tract urothelial cancer.SummaryThe bladder cancer molecular subtypes were associated with different prognoses and responses to conventional and targeted therapies in retrospective studies. If validated in prospective studies, molecular subtyping will be integrated into bladder cancer clinical management.

Purpose of ReviewThis study aimed to summarize evidence published between 1999 and June 2020 examining diet and lifestyle after prostate cancer (PC) diagnosis in relation to risk of biochemical recurrence, PC progression, and PC-specific mortality.Recent FindingsSecondary prevention is an important research area in cancer survivorship. A growing number of studies have reported associations between post-diagnostic modifiable behaviors and risk of PC outcomes.SummaryEvidence on modifiable lifestyle factors and PC remains limited. Where multiple studies exist, findings are often mixed. However, studies consistently suggest that smoking and consumption of whole milk/high-fat dairy are associated with higher risk of PC recurrence and mortality. In addition, physical activity and ½ to 1 glass of red wine/day have been associated with lower risk of recurrence and PC-specific mortality. Greater inclusion of racially/ethnically diverse groups in future research is necessary to understand these relationships in populations most impacted by adverse PC outcomes.

Purpose of ReviewTherapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.Recent FindingsThe first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with pancreatic or lung metastases, or previously undergoing organ transplantation and elderly subjects.SummarySome selected categories of patients may still benefit from monotherapy with TKI, and smart sequential therapies can also be considered instead of a combination strategy. Tyrosine kinase inhibitors can also act as immune modulator agents, boosting the immune response to facilitate and potentiate the therapeutic effectiveness of subsequent immunotherapy.

Abstract Purpose of ReviewHistorically, kidney cancer was diagnosed as either clear cell renal carcinoma (ccRCC) or non-clear cell renal carcinoma (nccRCC). With further research into the pathophysiology of nccRCC, multiple distinct subtypes have emerged creating distinct diagnosis, such as papillary renal cell carcinoma (PRCC), chromophobe renal cell carcinoma (crRCC), or unclassified carcinoma (cRCC). Many other kidney cancer subtypes are now included in the WHO classification system.Recent FindingsThe prognosis for each of the more frequently diagnosed types is discussed here along with treatment recommendations. The available clinical trial results and salient retrospective studies of each subtype are reviewed here to guide clinicians on the optimal treatment selection for patients with these rare histologic types or RCC.SummaryMany nccRCC types are now recognized and each has unique molecular drivers which are different than ccRCC. The optimal treatment strategy is different for each subtype. The prognosis also differs based on the histology.

Purpose of ReviewPatient reported outcomes (PROs) are increasingly utilized in cancer drug development, and are of particular importance in genitourinary cancers due to symptom burden, multiple treatment options with similar efficacy, and often prolonged duration of disease. Here we review current data and perspectives related to use of PROs in drug development for genitourinary cancers, including insights on the regulatory process for drug approval.Recent FindingsThe FDA is committed to incorporating PRO data into the regulatory process for development and approval of new cancer drugs, but challenges exist due to lack of standardization of PRO instrument choice and analytic approach, missing data, and difficulty isolating treatment effect from disease-related effects. We review guidance for standardization of PRO methodology that is nonetheless tailored to disease state and anticipated effects of treatment. PRO and efficacy data should be simultaneously analyzed and reported for best clinical practice. Multiple disease-specific PRO instruments exist for genitourinary cancers.SummaryWhile clinicians, researchers, and regulatory bodies alike recognize the importance of PROs in cancer drug development, challenges remain regarding implementation of best practices.

Purpose of ReviewDue to the rapidly changing field of kidney cancer therapeutics, addressing the state of the art systemic therapy regimens, and sequencing with cytoreductive nephrectomy are the primary focus of this review. We will also discuss the role of biomarkers and novel therapeutic targets in the management of renal cell carcinoma.Recent FindingsThe management of metastatic renal cell cancer has undergone a paradigm shift with immune checkpoint inhibitors being used in the frontline setting. Over the last 4 years, programmed cell death-1 (PD-1) inhibitors as well as programmed cell death ligand-1 inhibitors have become available in various combinations with cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors and tyrosine kinase inhibitors (TKIs). These drugs have improved outcomes in patients with renal cell cancer and more work is being done to refine these targets as well as discover newer ones.SummaryDespite the availability of several new treatment options, some questions that still need to be addressed in the management of kidney cancer include the sequencing of treatment options, treatment of patients who progress on immune checkpoint inhibitors, and role of biomarkers to ascertain the best treatment options to minimize costs and improve outcomes.

Purpose of ReviewThis review will examine the taxonomy of PCa subclasses across disease states, explore the relationship among specific alterations, and highlight current clinical relevance.Recent FindingsProstate cancer (PCa) is driven by multiple genomic alterations, with distinct patterns and clinical implications. Alterations occurring early in the timeline of the disease define core subtypes of localized, treatment-naive PCa. With time, an increase in number and severity of genomic alterations adds molecular complexity and is associated with progression to metastasis. These later events are not random and are influenced by the underlying subclasses.SummaryAll the subclasses of localized disease initially respond to androgen deprivation therapy (ADT), but with progression to castrate-resistant PCa (CRPC), mechanisms of resistance against ADT shift the molecular landscape. In CRPC, resistance mechanisms largely define the biology and sub-classification of these cancers, while clinical relevance and opportunities for precision therapy are still being defined.

Purpose of ReviewDespite significant progress, patients with metastatic prostate cancer continue to have poor prognosis. Immunotherapy has revolutionized cancer care for many tumor types but has a limited role in the treatment of prostate cancer. This review discusses the promise of immunotherapy in prostate cancer treatment with an emphasis on emerging therapeutic targets.Recent FindingsMost prostate tumors have low tumor mutational burden and lack immunogenicity, representing significant hurdles to induction of anti-tumor immunity. However, recent research centered on deciphering key mechanisms of immune resistance in the prostate tumor microenvironment has led to the discovery of a range of new treatment targets. These discoveries are currently being translated into innovative immunotherapy clinical trials for patients with prostate cancer. Recent progress includes early evidence of activity for these novel approaches and the identification of potential predictive biomarkers of response.SummaryNovel treatment strategies using new antigen-directed therapies, drugs targeting the immunosuppressive tumor microenvironment, and combination immunotherapy therapies show great potential and are currently in clinical development. In addition, a deeper understanding of predictors of response and resistance to immunotherapy in prostate cancer is allowing for a more personalized approach to therapy.