Hospitalizations Among Veterans Treated for Metastatic Prostate Cancer With Abiraterone or Enzalutamide.

BACKGROUND: Abiraterone and enzalutamide are second generation androgen receptor pathway inhibitors (ARPIs) used to treat advanced or metastatic prostate cancer. Without head-to-head comparative studies identifying 1 agent as preferred initial therapy, physician preferences guide initial ARPI choice. This study compares hospitalizations among patients treated initially with abiraterone versus enzalutamide. PATIENTS AND METHODS: United States veterans treated with abiraterone or enzalutamide between May 13, 2011 and December 31, 2019; then compared hospitalization rate during first treatment with ARPI in the Veterans Healthcare Administration. Baseline incidence rate of hospitalization was determined from data 1 year prior to ARPI. Incidence Rate Difference (IRD) was calculated using χ2 test and difference in IRD using Poisson Regression. RESULTS: 19,775 veterans were identified; 13,527 (68.4%) were initially treated with abiraterone and 6248 (31.6%) initially with enzalutamide. The enzalutamide cohort was older (75.8 vs. 74.5 years, P < .001) and had higher baseline comorbidities at ARPI initiation (4.4 vs. 4.0, P < .001). Patients were treated with enzalutamide longer than abiraterone (median 9.0 vs. 8.0 months, P < .001). Total hospitalizations increased from 465 per 1000 person-years in the year prior to treatment with abiraterone to 567 during treatment. Total hospitalizations increased from 417 per 1000 person-years in the year prior to treatment with enzalutamide to 430 during treatment. Total rate of hospitalization increased 22% for abiraterone compared to a 3% increase for enzalutamide in the 12 months after ARPI initiation (P < .0001). Abiraterone was associated with greater increase in rates of acute heart failure, atrial fibrillation, acute kidney injury, urinary tract infections, sepsis, and pneumonia. CONCLUSION: By comparing the rate of hospitalization before vs. during treatment, real world analyses identified a 22% versus 3% increase in hospitalizations with abiraterone compared to enzalutamide respectively, despite being used in a younger population with less comorbid disease. Abiraterone was also associated with higher risk of infections, a novel finding.

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Abiraterone acetate and enzalutamide are two common therapies for metastatic castration-resistant prostate cancer (mCRPC) that have shown improved overall survival (OS). The drugs have different mechanisms of action with limited comparative trials to evaluate treatment in patients with comorbidities such as obesity and diabetes. This is important since abiraterone requires the co-administration of prednisone. We assessed the relationship between body mass index (BMI), hemoglobin A1c (HbA1c), treatment, and survival in mCRPC. METHODS: Veterans treated with abiraterone or enzalutamide within the Veterans Health Administration between September 10, 2014 and June 2, 2017 with BMI and HbA1c were identified. Additional variables included age, baseline prostate-specific antigen at first treatment for mCRPC, race, and the Charlson comorbidity index. Differences in survival were compared using the Kaplan-Meier method. Cox proportional hazards regression modeling was used to assess the association between initial treatment, BMI, and HbA1c while adjusting for confounding variables. RESULTS: A total of 5231 patients were identified with a mean age of 75.2 years and 1241 (23.7%) were of black race. BMI was associated with OS with longest median survival of 29.8 months in BMI ≥ 30 (n = 1903), 23.9 months in BMI 25-30 (n = 1879), 15.9 months in BMI 18.5-25 (n = 1336), and 9.2 months in BMI < 18.5 (n = 113, p < 0.001). In a multivariable model compared to normal BMI, increased mortality was observed in BMI < 18.5 (adjusted hazard ratio (aHR) = 1.583, 95% confidence interval [CI]: 1.29-1.94) and a decreased mortality in BMI 25-30 (aHR = 0.751, 95% CI: 0.69-0.81) and BMI > 30 (aHR = 0.644, 95% CI: 0.59-0.70). In 3761 patients with BMI > 25, there was longer OS in patients treated with enzalutamide (28.4 months, n = 1615) compared to abiraterone (25.8 months, n = 2146, p = 0.002). In 1470 patients with BMI < 25, there was no difference in OS between patients treated with enzalutamide (16.0 months, n = 597, p = 0.513) or abiraterone (16.1 months, n = 873). In 1333 veterans with HbA1c ≥ 6.5%, initial prescription of enzalutamide was associated with longer OS compared with abiraterone (24.4 vs. 20.5 months, p = 0.0005). In 2088 patients with HbA1c < 6.5%, there was no difference in OS in patients who were initially prescribed enzalutamide versus abiraterone (25.7 vs. 23.5 months, p = 0.334). CONCLUSIONS: In veterans with mCRPC, increased BMI was associated with longer survival. Veterans with BMI > 25 had longer survival with enzalutamide compared to abiraterone. In patients with HbA1c ≥ 6.5%, enzalutamide was associated with longer survival compared to abiraterone. These results may facilitate prognostication of survival and improve treatment selection based on patient comorbidities.

Phosphorylation of the Gα protein Gpa2 promotes protein kinase A signaling in yeast.

Heterotrimeric G proteins are important molecular switches that facilitate transmission of a variety of signals from the outside to the inside of cells. G proteins are highly conserved, enabling study of their regulatory mechanisms in model organisms such as the budding yeast Saccharomyces cerevisiae Gpa2 is a yeast Gα protein that functions in the nutrient signaling pathway. Using Phos-tag, a highly specific phosphate binding tag for separating phosphorylated proteins, we found that Gpa2 undergoes phosphorylation and that its level of phosphorylation is markedly increased upon nitrogen starvation. We also observed that phosphorylation of Gpa2 depends on glycogen synthase kinase (GSK). Disrupting GSK activity diminishes Gpa2 phosphorylation levels in vivo, and the purified GSK isoforms Mck1 and Ygk3 are capable of phosphorylating Gpa2 in vitro Functionally, phosphorylation enhanced plasma membrane localization of Gpa2 and promoted nitrogen starvation-induced activation of protein kinase A. Together, the findings of our study reveal a mechanism by which GSK- and nutrient-dependent phosphorylation regulates subcellular localization of Gpa2 and its ability to activate downstream signaling.