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Background: Androgen signaling is central to prostate cancer and men’s health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). Methods: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n= 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. Results: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3rs12529, CYP17A1rs6162, SRD5A2rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p= 0.02), visceral adipose tissue index (VATi, p= 0.03), and BMI (p= 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r= 0.47) and SATi (r= 0.48). Conclusion: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

Background: Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis to the adrenal glands, while not as common, does occur. The biology that accounts for adrenal metastases may be attributed to the unique local steroid metabolome and co-clinical characterization may elucidate the role steroid biosynthesis plays in PCa progression. Methods: Three patients with metastatic PCa who had archived tumor tissue from an adrenalectomy were retrospectively identified, and one adrenal metastasis was developed into a xenograft (MDA-PCa-250). The adrenal metastases were characterized by performing somatic DNA whole exome sequencing (WES), RNA-Seq, immunohistochemistry (IHC), and steroid metabolite quantitation. The influence of steroid metabolites on adrenal metastasis cells and tumor growth was tested in vitro and in vivo. Results: Clinically, adrenalectomy was performed during castration-resistant oligometastatic disease, and two men experienced resensitization to leuprolide. Somatic DNA WES revealed heterogeneous alterations in tumor suppressor and DNA damage repair pathway genes. Adrenal metastases had active androgen receptor (AR) signaling by IHC, and RNA-Seq supported a potential role for adrenal androgen precursor metabolism in activating the AR. Steroid quantitation suggested the adrenal androgen precursors were converted into testosterone in these metastases, and stable isotope tracing of an organoid from MDA-PCa-250 confirmed the capability of adrenal metastases to biosynthesize testosterone from adrenal precursors. In vitro testing of a cell line derived from MDA-PCa-250 showed that testosterone and cortisol stimulated tumor cell growth. In vivo experiments demonstrated that MDA-PCa-250 grew in intact mice with circulating testosterone, but not in castrated mice. Conclusions: PCa adrenal metastases depend upon AR signaling driven by androgen precursors, androstenedione and dehydroepiandrosterone, available in the microenvironment, despite the presence of heterogeneous somatic DNA alterations. Moreover, MDA-PCa-250 provides a preclinical model that can recapitulate the unique androgen-dependence of adrenal metastases. Clinical trial registration: This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT01254864).

BACKGROUND: The introduction of immune checkpoint inhibitors rapidly changed treatment for patients with metastatic clear cell renal cell carcinoma (mRCC). First-line treatment now includes multiple immuno-oncology (IO) combinations that were approved over a short time period and were not directly compared in randomized clinical trials. Thus, clinicians face a challenge in individualizing first-line treatment to optimize clinical outcomes.OBJECTIVE: We sought to systematically review clinical outcomes for first-line IO combinations for patients with mRCC.METHODS: Literature reporting outcomes from phase III clinical trials that evaluated first-line IO combination therapies was identified through a search of the PubMed electronic database following PRISMA guidelines. Abstracts were screened to identify manuscripts that fit the search criteria, and then, a descriptive review was performed.RESULTS: Our literature search identified 2,229 abstracts that met the initial search criteria, and then, it was narrowed to 431 abstracts using filters for “clinical trial” and a “ten year” time window. After review of the abstracts, six manuscripts were selected for data extraction and subsequent review.CONCLUSION: When compared to sunitinib, four IO combinations improved overall survival as first-line treatment, and five improved progression free survival for patients with mRCC. These IO combination therapies have unique characteristics, so clinicians should take into account patient and cancer factors to individualize treatment recommendations.

The introduction of immune checkpoint inhibitors rapidly changed treatment for patients with metastatic clear cell renal cell carcinoma (mRCC). First-line treatment now includes multiple immuno-oncology (IO) combinations that were approved over a short time period and were not directly compared in randomized clinical trials. Thus, clinicians face a challenge in individualizing first-line treatment to optimize clinical outcomes. We sought to systematically review clinical outcomes for first-line IO combinations for patients with mRCC. Literature reporting outcomes from phase III clinical trials that evaluated first-line IO combination therapies was identified through a search of the PubMed electronic database following PRISMA guidelines. Abstracts were screened to identify manuscripts that fit the search criteria, and then, a descriptive review was performed. Our literature search identified 2,229 abstracts that met the initial search criteria, and then, it was narrowed to 431 abstracts using filters for “clinical trial” and a “ten year” time window. After review of the abstracts, six manuscripts were selected for data extraction and subsequent review. When compared to sunitinib, four IO combinations improved overall survival as first-line treatment, and five improved progression free survival for patients with mRCC. These IO combination therapies have unique characteristics, so clinicians should take into account patient and cancer factors to individualize treatment recommendations.

Renal medullary carcinoma (RMC) with associated sickle hemoglobinopathy frequently presents with hematuria and is likely to spread to the retroperitoneal lymph nodes. Survival outcomes for SMARCB1-deficient RMC are improving with contemporary management.

No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis.

First-line treatment of metastatic renal cell carcinoma (mRCC) has incrementally evolved over the past decade. Most recently, promising clinical trials for first-line cabozantinib, nivolumab plus ipilimumab, and bevacizumab plus atezolizumab were reported. However, the comparator arm in all of these trials was sunitinib, so no head-to-head comparison exists for contemporary first-line treatments. To provide an indirect comparison of first-line treatments for mRCC that are currently approved or likely soon to be approved. Pivotal phase 2/3 clinical trials comparing currently approved first-line agents and novel regimens of nivolumab plus ipilimumab and bevacizumab plus atezolizumab were included if they reported overall survival (OS), progression-free survival (PFS), or objective response rate (ORR). Network meta-analysis of OS, PFS, and ORR was conducted in the context of Bayesian hierarchical log-linear models with both within and between study variance components. For OS, evidence suggests nivolumab plus ipilimumab may be the best first-line treatment available for mRCC (probability best 52%). In contrast, cabozantinib may be superior to other first-line treatments for PFS (probability best 69%) and ORR (probability best 95%). For first-line treatment of mRCC, cabozantinib appears superior to other agents for PFS and ORR, whereas, nivolumab plus ipilimumab may be the best treatment for OS. No single agent was superior to comparators across all endpoints. First-line treatment for mRCC should be tailored to individual cases based on the unique characteristics of each treatment regimen.

Historically, tumor biopsies and clinical laboratory testing have been the gold standard for diagnosis and prognosis in metastatic renal cell carcinoma (mRCC). Genomic profiling in mRCC has traditionally been performed on tumor tissue; however, challenges and limitations in obtaining tissue biopsies led to the discovery of alternative biological specimens, namely circulating cell-free DNA (cfDNA). Rapidly evolving technologies, with increased sensitivity and specificity, have been used to query cfDNA in the clinical research setting. These investigations are rapidly establishing cfDNA and liquid biopsies as valuable complementary specimens to the gold standard, and in some instances surpassing these with unique insight into the contemporary genomic landscape and tumor heterogeneity. In this review, we will discuss recent research into the prognostic, diagnostic, and predictive utility of liquid biopsies in mRCC. We will explore their potential role in precision treatment of mRCC and conclude with what is needed in order to translate them to clinical practice.

Historically, tumor biopsies and clinical laboratory testing have been the gold standard for diagnosis and prognosis in metastatic renal cell carcinoma (mRCC). Genomic profiling in mRCC has traditionally been performed on tumor tissue; however, challenges and limitations in obtaining tissue biopsies led to the discovery of alternative biological specimens, namely circulating cell-free DNA (cfDNA). Rapidly evolving technologies, with increased sensitivity and specificity, have been used to query cfDNA in the clinical research setting. These investigations are rapidly establishing cfDNA and liquid biopsies as valuable complementary specimens to the gold standard, and in some instances surpassing these with unique insight into the contemporary genomic landscape and tumor heterogeneity. In this review, we will discuss recent research into the prognostic, diagnostic, and predictive utility of liquid biopsies in mRCC. We will explore their potential role in precision treatment of mRCC and conclude with what is needed in order to translate them to clinical practice.

Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) are a mainstay of treatment for metastatic renal-cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. Antibiotics targeting Bacteroidesspecies are associated with improved progression-free survival while receiving first-line VEGF-TKIs.

Background: First-line treatment of metastatic renal cell carcinoma (mRCC) has incrementally evolved over the past decade. Most recently, promising clinical trials for first-line cabozantinib, nivolumab plus ipilimumab, and bevacizumab plus atezolizumab were reported. However, the comparator arm in all of these trials was sunitinib, so no head-to-head comparison exists for contemporary first-line treatments.Objective: To provide an indirect comparison of first-line treatments for mRCC that are currently approved or likely soon to be approved.Methods: Pivotal phase 2/3 clinical trials comparing currently approved first-line agents and novel regimens of nivolumab plus ipilimumab and bevacizumab plus atezolizumab were included if they reported overall survival (OS), progression-free survival (PFS), or objective response rate (ORR). Network meta-analysis of OS, PFS, and ORR was conducted in the context of Bayesian hierarchical log-linear models with both within and between study variance components.Results: For OS, evidence suggests nivolumab plus ipilimumab may be the best first-line treatment available for mRCC (probability best 52%). In contrast, cabozantinib may be superior to other first-line treatments for PFS (probability best 69%) and ORR (probability best 95%).Conclusion: For first-line treatment of mRCC, cabozantinib appears superior to other agents for PFS and ORR, whereas, nivolumab plus ipilimumab may be the best treatment for OS. No single agent was superior to comparators across all endpoints. First-line treatment for mRCC should be tailored to individual cases based on the unique characteristics of each treatment regimen.

The HSD3B1(1245C) variant is predictive of response to ADT in castration sensitive prostate cancer (CSPC) and to ketoconazole in castration resistant prostate cancer (CRPC). We hypothesized that the HSD3B1(1245C) variant would be predictive of response to abiraterone acetate (AA). In 76 men with metastatic CRPC, the HSD3B1(1245C) variant was not predictive of response to first-line AA.

Antiandrogen withdrawal syndrome (AAWS) is a well-reported phenomenon with first-generation antiandrogens. AAWS is a less well-defined phenomenon with the antiandrogen enzalutamide. The present retrospective evaluation of men with progression during enzalutamide therapy failed to demonstrate a clinically significant incidence of enzalutamide withdrawal. These findings argue against the need to account for AAWS with enzalutamide in clinical trial designs.

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell types. In this mini-review, we describe new cancer cell–extrinsic roles for AR within the tumor microenvironment as well as systemic effects that collectively impact prostate cancer progression and patient outcomes.

ABSTRACTPreviously a malignancy with few therapeutic options, metastatic renal cell carcinoma (mRCC) treatment is rapidly evolving. Although cytokine therapies (interferon-a, interleukin-2) have been used less frequently over the past decade, recent approval of an immune checkpoint inhibitor, nivolumab, has led to a resurgence in immune therapy for mRCC. With greater understanding of the complex and dynamic interaction between the tumor and the immune system, numerous new immunotherapies are being studied for mRCC. In this article, we review the mechanism of action, clinical outcomes and toxicity profiles of both clinically approved and selected investigational immunotherapies. Either alone or in combination, these novel agents are encouraging for the future of mRCC therapy.

Antimicrobial drug-resistance continues to force adaptation in our clinical practice. We explore new evidence regarding adjunctive antibiotic therapy for skin and soft tissue abscesses as well as duration of therapy for intra-abdominal abscesses. As new evidence refines optimal practice, it is essential to support clinicians in adopting practice patterns concordant with evidence-based guidelines. We review a simple approach that can ‘nudge’ clinicians towards concordant practices. Finally, the use of novel antimicrobials will play an increasingly important role in contemporary therapy. We review five new antimicrobials recently FDA-approved for use in drug-resistant infections: dalbavancin, oritavancin, ceftaroline, ceftolozane-tazobactam, and ceftazidime-avibactam.

: Phase 1 clinical trials are important in developing novel therapies for patients with metastatic urothelial carcinoma (mUC), and prognostic scores may improve patient selection for enrollment in these studies. We evaluated urothelial carcinoma specific (Bellmunt, Bajorin) and phase 1 specific (Royal Marsden Hospital (RMH), MD Anderson Cancer Center (MDACC)) prognostic scores in a cohort of 57 trial participants (TPs) enrolling in phase 1 clinical trials. The RMH and MDACC phase 1 prognostic scores accurately predicted survival in patients with mUC and outperformed the urothelial carcinoma-specific scores at time of enrollment on phase 1 clinical trials. Our findings suggest that the RMH and MDACC prognostic scores could optimize selection of patients with mUC for phase 1 clinical trials.