Enzalutamide–Leuprolide Combination in Recurrent Prostate Cancer
A phase 3 study has demonstrated that in patients with prostate cancer with high-risk biochemical disease resurgence, combination treatment with enzalutamide plus leuprolide was superior to leuprolide alone in producing metastasis-free survival. Approximately 20% to 50% of patients who have undergone definitive treatment for prostate cancer experience such biochemical disease resurgence, characterized by a rise in prostate-specific antigen (PSA) levels. Patients whose PSA levels double in less than a 9-month period are at high risk for rapid disease progression.
READ MORE...
The EMBARK trial evaluated the efficacy and safety of enzalutamide plus leuprolide and enzalutamide monotherapy as compared with leuprolide alone in patients with prostate cancer who had high-risk biochemical resurgence. Patients were randomly assigned to enzalutamide plus leuprolide (combination group, n = 355), placebo plus leuprolide (leuprolide-only group, n = 358), and placebo plus enzalutamide (monotherapy group, n = 355). Enzalutamide (160 mg) and placebo were given orally once daily; leuprolide (2.25 mg) as a single IM or subut injection every 12 weeks. Patients were recruited from 244 sites in 17 countries; eligible patients had confirmed adenocarcinoma of the prostate, with high-risk disease, defined as PSA doubling time of 9 months or less and PSA levels of more than 2 ng/mL above nadir after radiation treatment or at least 1 ng/mL after radical prostatectomy.
At 5 years, metastasis-free survival was 87.3% in the combination group, 71.4% in the leuprolide-only group, and 80.0% in the monotherapy group. Combination treatment had a 57.6% lower risk of metastasis or death (hazard ratio [HR], 0.42); monotherapy was also superior to leuprolide alone, with a 36.9% lower risk (HR, 0.63). These differences were statistically significant. Death or disease progression on imaging occurred in 45 patients (12.7%) in the combination group, 92 patients (25.7%) in the leuprolide-only group, and 63 patients (17.7%) in the monotherapy group. Those free from PSA progression at 5 years numbered 97.4% of those on combination therapy, 70% of those receiving leuprolide only, and 88.9% of those on enzalutamide monotherapy.
Treatment was suspended at week 37 if PSA reached undetectable levels (less than 0.2 ng/mL). In the combination group, 90.9% of patients (321/353) had reached undetectable PSA levels; treatment was suspended for a median of 20.2 months in that group. In the leuprolide-only group, 67.8% of patients (240/354) had achieved undetectable PSA levels; treatment was suspended for a median of 16.8 months. In the monotherapy group, 85.9% of patients (304/354) had achieved undetectable PSA levels; treatment was suspended for a median of 11.1 months.
The median duration of treatment was 38.7 months, with no new safety issues reported. The most common adverse events were hot flashes, fatigue, and (in monotherapy group) gynecomastia. Most were less than grade 3 in severity. Treatment was discontinued due to adverse events in 20.7% in the combination group, 10.2% in the leuprolide-only group, and 17.8% in the monotherapy group. The most common cause leading to discontinuation was fatigue.
The magnitude of risk reduction for metastases and death seen in this study is consistent with the additional benefit provided by the addition of enzalutamide to treatment for metastatic hormone-sensitive prostate cancer. (Freedland, S. J., et al. (2023). Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. New Engl J Med, 389, 1453–1465 https://www.nejm.org/doi/full/10.1056/NEJMoa2303974?logout=true)
Released: November 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Insulin Pumps and Intensive Education Program Improve Hb A1c in Pediatric Diabetes
Compared with matched persons receiving other forms of intensive insulin treatment, pediatric patients with type 1 diabetes mellitus on insulin pumps have lower glycosylated hemoglobin (Hb A1c) levels. A longitudinal study published in Archives of Disease in Childhood examined the impact, not only of intensive insulin treatment, but also of multidisciplinary team input, on glycemic control. Use of intensive insulin treatment, including insulin pumps and multiple daily injections (MDIs), has replaced the use of fixed-dose regimens in the management of diabetes. This study compared these two regimens and further analyzed the effectiveness of an active intervention program (AIP), a diabetes nurse specialist-led service that offered contact, extra support, and education to any patient with poor or deteriorating glycemic control.
READ MORE...
The study examined a prospectively maintained database of clinical encounters from a large tertiary pediatric diabetes center in Ireland over a 13-year period; that center has a long-standing history of improved access to insulin pump treatment complemented by multidisciplinary team support. The dataset consisted of 25,865 encounters for 1,359 patients; the study examined data only for patients with type 1 diabetes mellitus; after excluding encounters that did not include measurement of Hb A1c and those without a certain date of diagnosis, the study ultimately examined 15,284 encounters with 995 patients.
A sustained improvement in Hb A1c was observed in the insulin pump cohort that was evident as early as 6 months. By 1 year, relative to the MDI cohort, the Hb A1c with insulin pump use was 7.47% versus 8.00%, a decrease of 0.53%. This improvement was sustained over 8 years (Hb A1c 7.8% versus 8.32%, a decrease of 0.53%). The Hb A1c in patients who were assigned to receive AIP along with the intensive insulin therapy was an average 0.95% higher than otherwise identical patients. After 6 months of the AIP sessions, Hb A1c dropped by a mean of 0.81%, a finding that was consistent no matter which forms of intensive insulin therapy were used.
Results of this study demonstrate that, although new technologies for delivery of insulin therapy have a significant role to play in glycemic control, so too does the action of the diabetes nurse educator and the multidisciplinary team. This study was limited by its focus on Hb A1c alone, as other factors can influence the development of long-term diabetes complications. The authors stress that the multidisciplinary team will continue to need support and resources to meet the needs of their pediatric patients. (Foran, J., et al. (2023). Close intervention sessions complement intensive insulin therapy in paediatric diabetes: A longitudinal study. Arch Dis Child, 108, 818–823. https://adc.bmj.com/content/108/10/818)
Released: November 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Current Therapies for Nonhospitalized COVID-19 Patients
Antivirals for nonhospitalized patients with COVID-19 infection prevent progression to severe illness, hospitalization, and death, but utilization of these therapies remains low. A viewpoint published in JAMA summarizes the available antivirals, and discusses which patients are most likely to benefit from them. Clinical trials conducted before widespread SARS-CoV2 vaccination and before the widespread circulation of the omicron variants demonstrated the effectiveness of these treatments in preventing progression to severe COVID-19. After widespread immunization campaigns, the lower hospitalizations and death rates have made it difficult to assess current benefits. Recent retrospective analyses have, however, suggested that nirmatrelvir–ritonavir continues to have value in older persons and others who develop the infection.
READ MORE...
The combination antiviral nirmatrelvir–ritonavir (marketed as Paxlovid) was approved by the FDA in May 2023 for treatment of mild to moderate COVID-19 in adults at high risk of progression. The oral SARS-CoV2 protease inhibitor is given within 5 days of symptom onset and is taken twice daily for 5 days; it has been shown to reduce hospitalization and death by 86%. It's considered safe to use in pregnant patients, and its use is limited only by the action of ritonavir on cytochrome P3A4, which results in numerous potential drug interactions.
Remdesivir, a nucleotide prodrug that inhibits viral RNA polymerase, has been approved for use in adult and pediatric patients 28 days or older at high risk for progression to severe COVID-19. It's given as soon as possible after diagnosis, within 7 days of symptom onset, via IV infusion once daily for 3 days. It also was shown in trials to reduce hospitalization or death by 87% compared with placebo. Its use in pregnancy is not recommended; in general, the need to administer remdesivir IV limits its accessibility for many patients.
Molnupiravir, an oral agent that inhibits viral replication by inducing viral RNA mutagenesis, is given twice daily for 5 days. It's substantially less effective than other antivirals, reducing hospitalizations by 30% compared to placebo in clinical trials. It is not recommended for use in children or during pregnancy, but it is an option for adults at risk for progression to more severe COVID-19 infection for whom the other treatment options are inappropriate or are unavailable.
When choosing between these options, the prescriber must take patient characteristics into consideration. Although nirmatrelvir–ritonavir is the preferred agent, it may not be possible to use it because of serious drug interactions or in patients with severe kidney disease. Remdesivir is the next preferred choice, although administering 3 days of IV treatment presents challenges for many patients. Molnupravir should only be used if the other antivirals aren't accessible or are inappropriate, and only with patient counseling. (Chew, K. W., et al. (2023). COVID-19 therapeutics for nonhospitalized patients–Updates and future directions. JAMA, 330(16), 1519–1520. https://jamanetwork.com/journals/jama/article-abstract/2810358)
Released: November 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer