Adrenal Metastases as Sanctuary Sites in Advanced Renal Cancer

Involvement of the adrenal gland in kidney cancer represents a unique site of metastasis with a distinct clinical course. The cases are typically resistant to immune therapy and need local therapy management. A case series of patients with adrenal metastases was reviewed to highlight the nuances of clinical course and therapy. We reviewed renal cancer carcinoma (RCC) cases with adrenal metastases at Karmanos Cancer Center, Detroit MI. Medical records were reviewed to collect relevant case information. Next-generation sequencing, tumor mutation burden testing, and programmed death ligand biomarkers were evaluated in five cases. Twelve cases were reviewed; all were males with a median age of 49.5 years. Three patients presented with adrenal metastases only and were treated with local therapy. Three received interleukin-2 (IL-2). One patient relapsed with bilateral adrenal lesions after 11 years of remission, post-IL-2 therapy. Five cases received immune checkpoint inhibitor (ICI) and one received antivascular therapy. ICI therapy was followed by ablation of residual adrenal metastases in three patients. Genomic profiling was available in five cases. All were BAP1 and PD-L1 negative. Pathogenic mutations in PBRM1, SETD2, and VHL were noted. All patients with residual adrenal metastases responded to antivascular therapies or to local ablation. One patient died 17 years after diagnosis and 11 patients are alive at a median follow-up of 9.5 years. Adrenal metastases in RCC have a distinct clinical course. They can represent a sanctuary site of relapse/residual disease following treatment with immune therapy. Management with local therapy can induce durable remissions. Systemic management with antivascular therapies also demonstrated favorable responses. Further investigation should focus on the unique clinical course and optimal management of adrenal metastases in kidney cancer

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706

Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy

Abstract Background There is an unmet need to determine factors predictive of clinical benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC). We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as predictors of response rate, progression free survival (PFS) and overall survival (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). Methods Regulatory approval was obtained. A single center retrospective chart review of mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics, smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria), NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF therapy ≥6 months or <6. Results 42 patients were evaluated with median age of 61 years (range, 24-85). Pretherapy NLR < 3 and ≥3 was seen in 19 (45%) and 23 (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF inhibitors for a duration of ≥6 months and <6 months, respectively. 12 (29%), 22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease based on Heng criteria, respectively. Multivariable analysis showed pretherapy NLR ≥3 was predictive of shorter PFS and OS when treated with ICI with median 3.08 months and 13.50 months, respectively, versus 15.57 months and not reached for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF therapy <6 months was predictive of increased likelihood of benefit from ICI therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months, respectively, in cases with prior anti-VEGF therapy for ≥6 months and <6 months. Conclusion Pretherapy NLR <3 and duration of prior anti-VEGF therapy of <6 months, are independent statistically significant predictors of longer PFS and OS with ICI therapy in mRCC. Validation is required in a larger sample size with multi-institutional collaboration

Additional file 1: Table S1. of Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy

Univariable logistic and Cox regression analyses for RR, PFS, and OS. Table S2. Univariable and multivariable logistic and Cox regression analyses of risk factors associated with RR, PFS, and OS. Note ‘Pretherapy NLR’ is grouped by its median of 3.2. Table S3. Univariable and multivariable logistic and Cox regression analyses of risk factors associated with RR, PFS, and OS. Note ‘Pretherapy NLR’ is considered as a continuous variable. Table S4. Univariable and multivariable Cox regression analyses of risk factors associated with PFS. Note that two variables ‘Duration of prior anti-VEGF Therapies’ and ‘Pretherapy NLR (with the cutoff value of 3)’ are combined. Table S5. Univariable and multivariable Cox regression analyses of risk factors associated with PFS. Note that two variables ‘Duration of prior anti-VEGF Therapies’ and ‘Pretherapy NLR (with the cutoff value of 3.2 [median])’ are combined. Figure S1. The boxplot of pretherapy NLR by the duration of prior anti-VEGF therapies. The p-value is calculated using the Kruskal. (DOCX 38 kb