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A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA
Jianqing Lin1, Tingting Zhan2, Danielle Duffy3
1Department of Medical Oncology, Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
Background:
Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.
Methods:
An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3-24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 - 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.
Results:
Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.
Conclusions:
Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.
Insights
Digoxin showed a well-tolerated safety profile in prostate cancer patients, prolonging prostate-specific antigen doubling time (PSADT) in 38% of participants. However, its clinical benefit in biochemically relapsed prostate cancer appears limited compared to historical placebo data.
Area of Science:
- Oncology
- Pharmacology
- Cardiology
Background:
- Prostate cancer (PCa) growth may be inhibited by digoxin through HIF-1α synthesis inhibition, as observed in mouse models.
- A hypothesis proposed that therapeutic digoxin doses could inhibit human PCa growth and progression.
Purpose of the Study:
- To evaluate the efficacy and safety of digoxin in patients with biochemically relapsed prostate cancer.
- To assess the impact of digoxin on prostate-specific antigen doubling time (PSADT) and explore its effect on HIF-1α downstream markers.
Main Methods:
- An open-label, single-arm pilot study enrolled patients with non-metastatic, biochemically relapsed PCa and specific PSADT and testosterone levels.
- Digoxin was administered daily with dose titration to achieve therapeutic levels (0.8-2 ng/ml), with regular cardiac monitoring and digoxin level assessments.
- The primary endpoint was the proportion of patients achieving a PSADT ≥ 200% of baseline at 6 months; plasma vascular endothelial growth factor (VEGF) was also measured.
Main Results:
- Out of 16 enrolled patients, 14 completed 6 months of treatment. Three patients (20%) experienced a PSA decrease >25% lasting a median of 14 months.
- At 6 months, 38% (5/13) of patients achieved a PSADT ≥ 200% of baseline and continued treatment. Two patients showed durable PSA response >1 year.
- Digoxin was generally well-tolerated, with no toxicity observed. Some patients required dose reduction due to ECG changes (sinus bradycardia, QT prolongation). Plasma VEGF was detected in 25% of patients.
Conclusions:
- Digoxin was well-tolerated and demonstrated a prolongation of PSADT in 38% of patients with biochemically relapsed prostate cancer.
- The observed efficacy did not show a significant difference compared to historical placebo data for similar patient cohorts.
- The study suggests that digoxin, at the tested dose, may offer limited clinical benefit for patients with biochemically relapsed prostate cancer.
