Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex.

BACKGROUND: The sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown. OBJECTIVE: We performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. DESIGN: Prospective randomized placebo-controlled trial. PARTICIPANTS: A total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200-5000 mg/g) with and without type 2 diabetes. INTERVENTION: Dapagliflozin 10 mg versus placebo once daily. MAIN MEASURES: Primary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. KEY RESULTS: Median follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope. CONCLUSIONS: Dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit. TRIAL REGISTRY: clinicaltrials.gov NIH TRIAL REGISTRY NUMBER: NCT03036150.

Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer.

BACKGROUND: Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined. METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival. RESULTS: A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group. CONCLUSIONS: In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.

BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

BACKGROUND: In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). METHODS: SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. FINDINGS: Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. INTERPRETATION: In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. FUNDING: Janssen Research & Development.

End-of-Life Care for Patients With Advanced Kidney Disease in the US Veterans Affairs Health Care System, 2000-2011.

BACKGROUND: Little is known about patterns of end-of-life care for patients with advanced kidney disease not treated with maintenance dialysis. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: A sample of 14,071 patients with sustained estimated glomerular filtration rates < 15mL/min/1.73m2 treated in the US Veterans Affairs health care system who died during 2000 to 2011. Before death, 12,756 of these patients had been treated with dialysis, 503 had been discussing and/or preparing for dialysis therapy, and for 812, there had been a decision not to pursue dialysis therapy. OUTCOMES: Hospitalization and receipt of an intensive procedure during the final month of life, in-hospital death, and palliative care consultation and hospice enrollment before death. RESULTS: Compared with decedents treated with dialysis, those for whom a decision not to pursue dialysis therapy had been made were less often hospitalized (57.3% vs 76.8%; OR, 0.40 [95% CI, 0.34-0.46]), less often the recipient of an intensive procedure (3.5% vs 24.6%; OR, 0.15 [95% CI, 0.10-0.22]), more often the recipient of a palliative care consultation (52.6% vs 21.6%; OR, 4.19 [95% CI, 3.58-4.90]), more often used hospice services (38.7% vs 18.2%; OR, 3.32 [95% CI, 2.83-3.89]), and died less frequently in a hospital (41.4% vs 57.3%; OR, 0.78 [95% CI, 0.74-0.82]). Hospitalization (55.5%; OR, 0.39 [95% CI, 0.32-0.46]), receipt of an intensive procedure (13.7%; OR, 0.60 [95% CI, 0.46-0.77]), and in-hospital death (39.0%; OR, 0.47 [95% CI, 0.39-0.56]) were also less common among decedents who had been discussing and/or preparing for dialysis therapy, but their use of palliative care and hospice services was similar. LIMITATIONS: Findings may not be generalizable to groups not well represented in the Veterans Affairs health care system. CONCLUSIONS: Among decedents, patients not treated with dialysis before death received less intensive patterns of end-of-life care than those treated with dialysis. Decedents for whom there had been a decision not to pursue dialysis therapy before death were more likely to receive palliative care and hospice.

Trends in the Timing and Clinical Context of Maintenance Dialysis Initiation.

Whether secular trends in eGFR at dialysis initiation reflect changes in clinical presentation over time is unknown. We reviewed the medical records of a random sample of patients who initiated maintenance dialysis in the Department of Veterans Affairs (VA) in fiscal years 2000-2009 (n=1691) to characterize trends in clinical presentation in relation to eGFR at initiation. Between fiscal years 2000-2004 and 2005-2009, mean eGFR at initiation increased from 9.8±5.8 to 11.0±5.5 ml/min per 1.73 m(2) (P<0.001), the percentage of patients with an eGFR of 10-15 ml/min per 1.73 m(2) increased from 23.4% to 29.9% (P=0.002), and the percentage of patients with an eGFR>15 ml/min per 1.73 m(2) increased from 12.1% to 16.3% (P=0.01). The proportion of patients who were acutely ill at the time of initiation and the proportion of patients for whom the decision to initiate dialysis was based only on level of kidney function did not change over time. Frequencies of documented clinical signs and/or symptoms were similar during both time periods. The adjusted odds of initiating dialysis at an eGFR of 10-15 or >15 ml/min per 1.73 m(2) (versus <10 ml/min per 1.73 m(2)) during the later versus earlier time period were 1.43 (95% confidence interval [95% CI], 1.13 to 1.81) and 1.46 (95% CI, 1.09 to 1.97), respectively. In conclusion, trends in eGFR at dialysis initiation at VA medical centers do not seem to reflect changes in the clinical context in which dialysis is initiated.

Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.

BACKGROUND: Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]). INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. FUNDING: Janssen Research & Development.

Associations between sex and incident chronic kidney disease in a prospective diabetic cohort.

AIM: Women with diabetes have a higher prevalence of chronic kidney disease (CKD) risk factors compared with men, but whether they are at higher risk for incident CKD remains uncertain. METHODS: This was a prospective, observational cohort study of 1464 patients with diabetes and normal renal function, recruited from primary care clinics at a vertically integrated healthcare system in Seattle, WA, USA. The primary predictor was sex. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2) by Chronic Kidney Disease-Epidemiology equations or sex-specific microalbuminuria (urine albumin/creatinine ratio ≥25 mg/g for women or ≥17 mg/g for men). RESULTS: Of the 1464 patients (52.0% women), CKD incidence rates were 154.0 and 144.3 cases per 1000 patient-years for women and men, respectively. In the competing risks regression, women had an increased risk of incident CKD (sub-hazard ratio 1.37, 95% confidence interval (CI) 1.17, 1.60) compared with men after adjustment for demographics, baseline eGFR and duration of diabetes, which persisted after additional adjustment for CKD risk factors, depressive symptoms and diabetes self-care (sub-hazard ratio 1.35, 95% CI 1.15, 1.59). Sex differences in incident CKD were consistent across age groups and appeared to be driven by differences in the development of low eGFR rather than microalbuminuria. CONCLUSION: Women with diabetes had a higher risk of incident CKD compared with men, which could not be entirely explained by differences in biologic CKD risk factors, depression or diabetes self-care. Additional work is needed determine if these sex differences contribute to worse outcomes in women with diabetes.

Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer.

Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.

Abiraterone acetate and prednisolone for metastatic castration-resistant prostate cancer failing androgen deprivation and docetaxel-based chemotherapy: a phase II bridging study in Korean and Taiwanese patients.

OBJECTIVES: To evaluate the safety and efficacy of abiraterone acetate and prednisolone in Korean and Taiwanese patients with metastatic castration-resistant prostate cancer not responding to docetaxel-based chemotherapy. METHODS: In this single-arm study, 82 metastatic castration-resistant prostate cancer patients who failed docetaxel-based chemotherapy were treated with abiraterone (1000 mg, once daily) and prednisolone (5 mg, twice daily). Patients achieving a prostate-specific antigen decline ≥ 50% were considered as responding. RESULTS: A total of 35 patients (43%) achieved prostate-specific antigen response (95% confidence interval 32-54). The median time to prostate-specific antigen progression was 4.7 months (95% confidence interval 3.7-8.3); the median overall survival was 11.8 months. Two (4%) of 50 patients with measurable disease achieved partial response. The median testosterone concentration was in the castration range (1.21 nmol/L) throughout the treatment period. Median dehydroepiandrosterone sulfate decreased from 0.725 µmol/L (baseline) to 0.080 µmol/L (cycle 4). The most common adverse event was bone pain (20%); grade 3/4 adverse event of special interest were hypokalemia (7%), fluid retention and liver function abnormalities (5% each), hypertension (2%), and cardiac disorders (1%). CONCLUSIONS: A combination of abiraterone acetate and prednisolone appears to be a favorable second-line treatment in Taiwanese and Korean patients with advanced metastatic castration-resistant prostate cancer after failed docetaxel-based chemotherapy.

Diabetes self-care, major depression, and chronic kidney disease in an outpatient diabetic population.

BACKGROUND/AIMS: The associations between major depression and chronic kidney disease (CKD) in patients with diabetes are incompletely characterized. Depressed patients with diabetes are known to have worse diabetes self-care, but it is not known whether this mediates the association between depression and CKD in this population. METHODS: We conducted a cross-sectional study of the associations between major depressive symptoms and CKD in the Pathways Study (n = 4,082), an observational cohort of ambulatory diabetic patients from a managed care setting. Depression status was ascertained using the Patient Health Questionnaire-9 (PHQ-9). Stepwise logistic regression models examined the associations between depression and impaired estimated glomerular filtration rate (<60 ml/min/1.73 m(2)) or microalbuminuria, after adjustment for demographics, CKD risk factors, and diabetes self-care variables. RESULTS: Clinically significant depression symptoms (PHQ-9 ≥10) were associated with a greater risk of microalbuminuria after adjustment for demographic variables (OR 1.54, 95% CI 1.21-1.95) and traditional CKD risk factors (OR 1.36, 95% CI 1.04-1.77); this association persisted after additional adjustment for diabetes self-care (OR 1.34, 95% CI 1.02-1.75). Depression was not associated with impaired estimated glomerular filtration rate in any of the models. CONCLUSION: In this cohort of diabetic subjects, clinically significant depression symptoms were associated with microalbuminuria, which could not be entirely explained by differences in diabetes self-care.

Risk factor, age and sex differences in chronic kidney disease prevalence in a diabetic cohort: the pathways study.

BACKGROUND/AIMS: Women with diabetes experience a disproportionately greater burden of diabetic kidney disease (DKD) risk factors compared to men; however, sex-specific differences in DKD are not well defined. The effect of age on sex differences in DKD is unknown. METHODS: We performed a cross-sectional analysis of the prevalence of DKD (eGFR <60 ml/min/1.73 m(2) or microalbuminuria), advanced DKD (eGFR <30 ml/min/1.73 m(2)), and common DKD risk factors in the Pathways Study (n = 4,839), a prospective cohort study of diabetic patients from a managed care setting. Subjects were stratified by age <60 and ≥60 years to examine for differences by age. Logistic regression models examined the association between sex and prevalence of DKD and risk factors. RESULTS: Women of all ages had 28% decreased odds of DKD (OR 0.72, 95% CI 0.62-0.83); however, they had a greater prevalence of advanced DKD (OR 1.67, 95% CI 1.05-2.64), dyslipidemia (OR 1.42, 95% CI 1.16-1.74), and obesity (OR 1.87, 95% CI 1.60-2.20) compared to men. Women had similar odds of hypertension and poor glycemic control as men. Women ≥60 years had increased odds of advanced DKD, hypertension, dyslipidemia, and obesity compared to similarly aged men. Women <60 years had increased odds of obesity compared to their male counterparts. CONCLUSION: Women with diabetes had an increased prevalence of advanced DKD and common DKD risk factors compared to men and these disparities were most prominent amongst the elderly.

Video Images about Decisions for Ethical Outcomes in Kidney Disease (VIDEO-KD): the study protocol for a multi-centre randomised controlled trial.

INTRODUCTION: Older patients with advanced chronic kidney disease (CKD) often are inadequately prepared to make informed decisions about treatments including dialysis and cardiopulmonary resuscitation. Further, evidence shows that patients with advanced CKD do not commonly engage in advance care planning (ACP), may suffer from poor quality of life, and may be exposed to end-of-life care that is not concordant with their goals. We aim to study the effectiveness of a video intervention on ACP, treatment preferences and other patient-reported outcomes. METHODS AND ANALYSIS: The Video Images about Decisions for Ethical Outcomes in Kidney Disease trial is a multi-centre randomised controlled trial that will test the effectiveness of an intervention that includes a CKD-related video decision aid followed by recording personal video declarations about goals of care and treatment preferences in older adults with advancing CKD. We aim to enrol 600 patients over 5 years at 10 sites. ETHICS AND DISSEMINATION: Regulatory and ethical aspects of this trial include a single Institutional Review Board mechanism for approval, data use agreements among sites, and a Data Safety and Monitoring Board. We intend to disseminate findings at national meetings and publish our results. TRIAL REGISTRATION NUMBER: NCT04347629.

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer.

IMPORTANCE: There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). OBJECTIVE: To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020. INTERVENTIONS: Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT. MAIN OUTCOMES AND MEASURES: Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04). CONCLUSIONS AND RELEVANCE: The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.

Impact of clinical versus radiographic progression on clinical outcomes in metastatic castration-resistant prostate cancer.

OBJECTIVES: Unequivocal clinical progression (UCP)-a worsening of clinical status with or without radiographic progression (RAD)-represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes. METHODS: A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS). RESULTS: Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p<0.0001). Median OS was 25.7 months in UCP-only and 33.0 months for RAD-only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP adversely impacted OS in both treatment groups. Lowest OS was seen in patients with prostate specific antigen (PSA)-non-response plus UCP-only progression (median OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP events lowered estimates of treatment benefit-median crPFS was 13.3 months (95% CI 11.1 to 13.8) versus median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP group. Finally, crPFS showed high correlation with OS (r=0.67; 95% CI 0.63 to 0.71). CONCLUSIONS: UCP is a common and clinically relevant phenomenon in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with AAP or prednisone. UCP is prognostic and associated with inferior OS and post-progression survival. A combination of PSA-non-response and UCP identifies patients with poorest survival. When included in PFS analysis, UCP diminishes estimates of treatment benefit. Continued study of UCP in mCRPC is warranted.

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study.

PURPOSE: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). PATIENTS AND METHODS: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. RESULTS: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. CONCLUSIONS: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer.

PURPOSE: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. PATIENTS AND METHODS: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. RESULTS: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. CONCLUSIONS: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.

Updates in Management and Timing of Dialysis in Acute Kidney Injury.

Acute kidney injury (AKI) is a common complication in hospitalized patients and is associated with mortality, prolonged hospital length of stay, and increased healthcare costs. This paper reviews several areas of controversy in the identification and management of AKI. Serum creatinine and urine output are used to identify and stage AKI by severity. Although standardized definitions of AKI are used in research settings, these definitions do not account for individual patient factors or clinical context which are necessary components in the assessment of AKI. After treatment of reversible causes of AKI, patients with AKI should receive adequate volume resuscitation with crystalloid solutions. Balanced crystalloid solutions generally prevent severe hyperchloremia and could potentially reduce the risk of AKI, but additional studies are needed to demonstrate a clinical benefit. Intravenous albumin may be beneficial in patients with chronic liver disease either to prevent or attenuate the severity of AKI; otherwise, the use of albumin or other colloids (eg, hydroxyethyl starch) is not recommended. Diuretics should be used to treat volume overload, but they do not facilitate AKI recovery or reduce mortality. Nutrition consultation may be helpful to ensure that patients receive adequate, but not excessive, dietary protein intake, as the latter can lead to azotemia and electrolyte disturbances disproportionate to the patient's kidney failure. The optimal timing of dialysis initiation in AKI remains controversial, with conflicting results from two randomized controlled trials.