Use of ZYTIGA in Patients with Diabetes

Prospective Study

Chowdhury et al (2020)⁷ evaluated the outcomes of patients with mCRPC and diabetes within a subset of patients receiving initial therapy with either ZYTIGA plus prednisone, enzalutamide, or docetaxel utilizing the PCR (n=1583).

Study Design/Methods

• Prospective, international, multicenter, real-world, observational study of 3003 patients with mCRPC and a history of progression despite testosterone <50 ng/dL, ADT, and/or history of orchiectomy in routine clinical practice (NCT02236637)
• This analysis of the PCR evaluated patients treated with ZYTIGA plus prednisone or prednisolone, enzalutamide, docetaxel, other chemotherapy, or radium223 as initial therapy for mCRPC.
• Outcome measures: TTP and OS

Results

Patient Characteristics

• Patients treated with other chemotherapy or radium-223 were excluded because the number of patients were too low.
• Select baseline characteristics for the patients who had not received previous mCRPC treatment at baseline and patients treated with first-line ZYTIGA plus prednisone are reported below in Table: Patient Characteristics.
• Among patients with diabetes receiving ZYTIGA plus prednisone (n=121), the median age was 77.0 years (range, 54-93) and 47.7% of patients had a Gleason score 8-10 at initial diagnosis.

Efficacy and Safety

• The median treatment duration was 11.2 months (95% CI, 9.8-12.2) and 11.5 months (95% CI, 9.1-16.1) in all patients receiving ZYTIGA plus prednisone and patients with diabetes receiving ZYTIGA plus prednisone, respectively.
• Outcomes for patients with diabetes receiving ZYTIGA plus prednisone compared to the total population included in the registry receiving ZYTIGA plus prednisone are reported below in Table: Efficacy Outcomes for Patients with mCRPC and Diabetes that Received ZYTIGA plus Prednisone.
• Safety data were not reported.

Post-Hoc Analyses of Pivotal Phase 3 Studies COU-AA-301 and COU-AA-302

Wilson et al (2022)⁶ conducted a post-hoc secondary analysis that evaluated the effect of metformin and statins on OS and PSA-RR in the ZYTIGA plus prednisone and placebo plus prednisone groups of the COU-AA-301 (N=1195) and COU-AA-302 (N=1088) studies.

• Results for metformin are provided below. Please refer to the publication for the complete analysis.
• In the COU-AA-301 study:
  • A total of 104 patients were reported to be taking metformin, 73 (9.2%) patients in the ZYTIGA plus prednisone group and 31 (7.8%) patients in the placebo plus prednisone group.
  • In the ZYTIGA plus prednisone group, there was no definitive association between median OS and patients taking vs not taking metformin in the univariate (19.4 months vs 15.6 months; HR, 0.76; 95% CI, 0.55-1.05; P=0.098) or multivariate (adjusted HR, 0.71; 95% CI, 0.5-1.006; P=0.054) analyses. The proportion of patients with PSA-RR was greater among patients taking vs not taking metformin (41.1% vs 28.6%; P=0.026).
  • In the placebo plus prednisone group, OS was not prolonged among patients taking vs not taking metformin in the univariate (14.0 months vs 11.1 months; HR, 0.85; 95% CI, 0.54-1.32; P=0.47) or multivariate (adjusted HR, 0.73; 95% CI, 0.46-1.15; P=0.17) analyses. There was no difference in PSA-RR among patients taking vs not taking metformin (3.2% vs 5.8%; P=0.55).
• In the COU-AA-302 study:
  • A total of 134 patients were reported to be taking metformin, 66 (12.1%) patients in the ZYTIGA plus prednisone group and 68 (12.5%) patients in the placebo plus prednisone group.
  • In the ZYTIGA plus prednisone group, there was no association between median OS and patients taking vs not taking metformin in the univariate analysis (not reached [NR] vs NR; HR, 0.81; 95% CI, 0.48-1.36; P=0.42); however, there was an association between prolonged OS and metformin use in the multivariate analysis (adjusted HR, 0.69, 95% CI, 0.48-0.98; P=0.039). The proportion of patients with PSA-RR was greater among patients taking vs not taking metformin (72.7% vs 60.0%; P=0.046).
  • In the placebo plus prednisone group, there was no association between a significant difference in OS and patients taking vs not taking metformin in the univariate analysis (NR vs 26.6 months; HR, 0.68; 95% CI, 0.42-1.11; P=0.12); however, there was an association between prolonged OS and metformin use in the multivariate analysis (adjusted HR, 0.66; 95% CI, 0.47-0.93; P=0.018). Additionally, there was no significant difference in PSA-RR among patients taking vs not taking metformin (27.9% vs 23.3%; P=0.41).
• After pooling HR across both studies and treatment groups, OS was prolonged among those treated with metformin (pooled HR, 0.77; 95% CI, 0.62-0.95).
• Between all groups, the rates of all AEs and grade 3 or 4 AEs were similar.
  • A higher number of grade 3 or 4 cardiac disorder and hypokalemia AEs were reported in patients taking statins with ZYTIGA plus prednisone vs patients not taking statins with ZYTIGA plus prednisone in COU-AA-301 (cardiac disorder, 8.5% vs 3.8%; hypokalemia, 6.8% vs 4.3%) and COU-AA-302 (cardiac disorder, 8.7% vs 3.2%; hypokalemia, 3.9% vs 1.6%).

Fizazi et al (2016)⁴ evaluated the safety of long-term use of prednisone, with or without ZYTIGA in patients with mCRPC from 2 randomized, phase 3, registration studies, COU-AA-301 and COU-AA-302 (N=2267). Patients received prednisone for a median of 8.3 months (range, 0.1-34.9 months). Incidence of any-grade CA-AEs after any prednisone exposure was 25%, 26%, and 23% for all patients, the ZYTIGA plus prednisone group, and the placebo plus prednisone group, respectively; incidence of grade ≥3 CA-AEs was 5%, 5%, and 4%, respectively. The most common, any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, ZYTIGA plus prednisone, and placebo plus prednisone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). Diabetes mellitus of any grade occurred in 1.1% of patients, inadequate control of diabetes in 0.2%, and impaired glucose tolerance in 0.1%. The 3 most common grade ≥3 CA-AEs were hyperglycemia (2.0%), cataract (0.4%) and diabetes mellitus (0.4%). The investigator-reported discontinuation rate due to CA-AEs was 0.6% (8/1333) for the ZYTIGA plus prednisone group and 0.3% (3/934) for the placebo plus prednisone group. Diabetes mellitus led to study discontinuation in 1 patient within the placebo plus prednisone group. One patient experienced a CA-AE resulting in death (in the COU-AA-301 study). The sponsor assessment of the cause of death was upper gastrointestinal hemorrhage.

Hamilton et al (2014)⁵ conducted an exploratory analysis evaluating the effect of concomitant medication use, including metformin, on OS in the treatment and placebo arms of COU-AA-301 and COU-AA-302. Initial assessments of concomitant metformin use revealed improved OS (COU-AA-301, P=0.0263; COU-AA-302, P=0.084). Multivariate analysis was not performed due to low numbers of patients and imbalance between groups. No safety data were reported.

Case Reports

Case reports were identified in the literature, each of which reported safety data following ZYTIGA plus steroid/prednisone/prednisolone use in a patient with diabetes.^8,10-16

Kasahara et al (2026)¹⁴ described a case report of an 83-year-old male patient with castration-resistant prostate cancer (CRPC) and a history of ischemic heart disease, mild dementia, and well-controlled type 2 diabetes mellitus who was admitted to the emergency room after a fall. Approximately 1 month earlier, he had started receiving ZYTIGA and steroid combination therapy for CRPC with multiple lung metastases. A blood test performed during the second week of treatment (a few days before the fall) revealed no abnormalities. Based on the patient's clinical presentation, blood test results, and treatment progress, ZYTIGA-induced liver injury was diagnosed, and he was urgently hospitalized. Treatment comprised intravenous fluids, antibiotics, and insertion of central venous and urinary catheters.

On day 11 of hospitalization, his laboratory tests showed increased serum creatinine
(2.06 mg/dL, which worsened to 3.98 mg/dL the next day), decreased urine output, and increased C-reactive protein (7.0 mg/dL). Abdominal non-contrast computed tomography (CT) scanning confirmed bilateral hydronephrosis and slightly dense masses at the site of obstruction on both sides. Hemodialysis was started on day 15. Blood and urine cultures confirmed C. albicans growth, and intravenous antifungal therapy with fosfluconazole was started on day 18. The patient’s condition improved with antifungal therapy and hemodialysis, and he was discharged on day 72 with good treatment progress.

Tumminia et al (2025)¹⁵ described a case report of a 68-year-old man with a 10-year history of type 2 diabetes mellitus and high blood pressure who was admitted for uncontrolled diabetes. He had been taking ZYTIGA 500 mg and prednisone 5 mg once daily in the morning since 2018. Laboratory tests revealed severe hypokalemia (2.2 mmol/L) and increased 24-hour urinary potassium excretion (147 mmol/24 h). His serum potassium levels did not improve despite oral and parenteral potassium supplementation.

A series of endocrine tests were performed to rule out Conn’s syndrome, primary aldosteronism, and renal artery stenosis. The patient had low renin levels (0.3 pg/mL; reference: 2.7-16.5 pg/mL), low aldosterone levels (1.9 pg/mL; reference: 2.235.5 pg/mL), and low serum cortisol levels (1.5 μg/dL; reference: 3.7-19.4 μg/dL) levels, while ACTH levels were high (193 pg/mL; reference: 10-60 pg/mL). Based on these findings, the patient was diagnosed with ZYTIGA-induced mineralocorticoid excess syndrome (MES). He was treated with amiloride (5 mg/day), and prednisone was replaced with dexamethasone 0.5 mg administered in the evening. The patient’s hypokalemia resolved quickly with this therapy, with renin levels returning to normal (2.4 pg/mL) and ACTH levels dropping to 45 pg/mL at discharge.

Fabros et al (2025)¹⁶ described a case report of a 79-year-old male with prostate carcinoma, bone metastases, hypertension, and diabetes with chronic kidney disease (CKD) who presented with a 2-week history of progressive weakness and dizziness. He had been receiving triptorelin pamoate every 6 months, ZYTIGA 250 mg twice daily, and prednisone 5 mg once daily for over a year. On admission, he had hypokalemia, his blood pressure was 200/100 mm Hg, and laboratory tests revealed renal potassium loss, metabolic alkalosis, low serum cortisol, and high ACTH, consistent with ZYTIGA-induced MES. Primary aldosteronism was ruled out based on a normal aldosterone-renin ratio. ZYTIGA was discontinued, prednisone was switched to dexamethasone, and finerenone was initiated. This treatment resolved MES, stabilized potassium levels, and improved blood pressure.

Vo et al (2022)⁹ described a case report of an 83-year-old man with a history of diabetes, hypertension, coronary artery disease, and prostate cancer with bone metastases who was admitted with a complicated urinary tract infection and a concurrent asymptomatic incidental coronavirus disease 2019 (COVID-19) infection. The patient had been receiving prostate cancer treatment for ≥10 years, consisting of ZYTIGA 1000 mg daily and prednisone 5 mg daily with an injection every 3 months. A urine culture report reported Pseudomonas mendocina with fluoroquinolone resistance. His urinary symptoms were completely resolved with a 7-day course of ceftriaxone and cefepime.

Tucci et al (2019)⁸ described 2 cases of severe hypoglycemia in patients with mCRPC and type 2 diabetes mellitus who received ZYTIGA plus prednisone, glucose-lowering agents, and statins. The first case report described a 69-year-old patient. After 2 weeks of treatment with ZYTIGA plus prednisone and gliclazide 200 mg/day, the patient reported symptomatic hypoglycemia episodes (minimum blood glucose level of 40 mg/dL in the morning fasting state). Gliclazide was reduced to 160 mg/day and was then replaced with glimepiride 2 mg/day due to persistent hypoglycemic episodes. Following the switch to glimepiride, no additional hypoglycemic episodes were reported, and the patient continued ZYTIGA plus prednisone. The second case report described a 79-year-old patient. After 5 days of treatment with ZYTIGA plus prednisone and repaglinide 4 mg/day, the patient experienced severe hypoglycemia (<30 mg/dL) that required hospitalization. ZYTIGA plus prednisone were stopped for 7 days and were then restarted along with repaglinide 2 mg/day. The patient then experienced severe hypoglycemic episodes, and repaglinide was stopped and substituted with insulin.

Kimata et al (2019)¹⁰ reported 2 cases of elderly patients with CRPC and diabetes receiving peritoneal dialysis. Both received ZYTIGA (750 mg orally once daily) and prednisolone (5 mg orally once daily). Although the prostate-specific antigen (PSA) level increased in both cases, there was no manifestation of disease progression (clinical and radiographic) for 22 months in case 1 and 8 months in case 2. The only >grade 3 AE reported for either patient was hypokalemia.

Schattner et al (2019)¹¹ described the case of a 74-year-old man with newly diagnosed metastatic prostate cancer and diabetes who experienced aortic dissection treated with interposition graft replacement and rehabilitation. He was receiving multiple medications including an antihypertensive, statin, metformin, and LHRH analog, and had received chest radiation. He had begun ZYTIGA plus prednisone 2 weeks prior to the event.

Rodieux et al (2015)¹² described 1 case report of a 74-year-old patient with hypertension, diabetes, anxiety disorder, and mCRPC who had life-threatening Torsades de Pointes associated with a prolonged QT interval and severe hypokalemia (2.5 mEq/L). The patient was taking ZYTIGA, in addition to other medications, and was found to have poor adherence to prednisone.

Neyra et al (2015)¹³ described a case report of a 76-year-old man with a history of type 2 diabetes, CKD, hypertension, hypothyroidism, antiphospholipid antibody syndrome, prior strokes, and metastatic prostate cancer who presented with rhabdomyolysis-induced acute kidney injury 3 weeks after receiving denosumab and ZYTIGA, in addition to multiple other chronic medications. The patient responded well to intravenous (IV) fluids with discontinuation of denosumab, ZYTIGA, and rosuvastatin, resulting in normalization of creatine kinase and recovery of kidney function.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 26 July 2026.

Additional studies of ZYTIGA have been published including patients with diabetes at baseline, or diabetes as identified as a comorbidity in a percentage of the study patients, but outcomes were not separately evaluated and reported for patients with diabetes. Retrospective studies, drug interaction evaluations, and real-world analyses were not included. Use of ZYTIGA in patients with cardiovascular disease, a common comorbidity in older patients with diabetes, is summarized as a separate topic and also addressed in product labeling.

REFERENCES