5-alpha reductase inhibitors (5-ARIs) and an increased risk of high grade prostate cancer

The Health Sciences Authority (HSA) would like to draw the attention of healthcare professionals to an increased risk of high grade prostate cancer observed in patients taking 5-alpha reductase inhibitors (5-ARIs) in clinical studies.

5-ARIs is a group of drugs with anti-androgenic activity that are licensed for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia. The two 5-ARIs available locally are dutasteride (Avodart®, GSK) and finasteride (Proscar® & Propecia®, MSD). Finasteride is also available as the generic brands, Finast® (Zyfas Medical Co.), Finas 1® (Apotheca Marketing Pte Ltd) and Finasteride Mevon® (Novem healthcare Pte Ltd).

Higher incidence of high grade prostate cancer observed in clinical trials

A recent review of two large, randomised controlled trials, namely the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, by the US Food and Drug Administration (FDA) indicated an increased incidence of high grade prostate cancer in patients treated with finasteride and dutasteride.¹ Although the risk appeared to be low, healthcare professionals are advised to be aware of this safety information and to weigh the benefits-risks of 5-ARIs before prescribing them.

A) Prostate Cancer Prevention Trial (PCPT)

PCPT was a randomised, double-blind, placebo-controlled study conducted in 18,882 men, aged 55 or older with a normal digital rectal examination and prostate-specific antigen (PSA) levels of 3ng/ml or less. Men who are at higher risk for developing prostate cancer, such as those with prior prostate biopsies demonstrating high-grade prostatic intra-epithelial neoplasia, were excluded from the study.

The study compared treatment with finasteride 5 mg (n=9,423) to placebo (n=9,459) taken daily for the reduction in the risk of prostate cancer. Treatment was continued for seven years following randomisation or until the diagnosis of prostate cancer, initiation of treatment with a 5-ARI for BPH, or when unacceptable side effects are experienced. During the study, trans-rectal ultrasound and sextant prostate biopsy were performed following the detection of an elevation in PSA level or an abnormal digital rectal examination. At the end of seven years, all participants who were not previously diagnosed with prostate cancer were asked to undergo trans-rectal ultrasound and sextant core prostate biopsy to check for prostate cancer.

Results of the PCPT showed that men in the finasteride arm had a 26% (p<0.0001) overall lower risk of being diagnosed with prostate cancer as compared to the placebo arm. However, the reduction in risk of prostate cancer was only limited to prostate cancer with a Gleason score (GS) 6 or lower. A small increased incidence in prostate cancers with GS 8 to 10 was observed with finasteride versus placebo (1.8% versus 1.1%, respectively).

B) Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial

REDUCE trial was a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of once daily dosing of dutasteride in reducing the risk of biopsy-detectable prostate cancer in men 50-75 years of age who are considered to be at increased risk for prostate cancer. A total of 8,231 men were randomised to receive either dutasteride 0.5 mg (n=4,105) or placebo (n=4,126) once daily for four years. Prostate biopsies were performed at 2 years and 4 years at the discretion of the investigator if clinically indicated.

Results of the trial showed that men on dutasteride had a 23% (p<0.0001) overall lower risk of being diagnosed with biopsy detectable prostate cancer when compared to men on placebo. This overall risk reduction was limited to a decrease in GS 6 or lower prostate cancers whereas a small increase in incidence of GS 8 to 10 prostate cancers with dutasteride versus placebo (1% versus 0.5%, respectively) was observed.

Local situation

HSA has not detected any signals of prostate cancer associated with the use of 5-ARIs in our local patients. To-date, we have received one suspected adverse drug reaction report of prostate cancer associated with the use of finasteride 1mg in a middle-aged male who has been taking finasteride 1mg daily for the treatment of male pattern hair loss. However, the causality could not be confirmed due to incomplete information.

HSA is working with the companies to ensure that the local package inserts of finasteride and dutasteride products are updated to reflect the higher incidence of high grade prostate cancers observed in clinical studies. Although the risk of high grade prostate cancers observed in the studies appeared to be low, physicians are advised to take into consideration the above safety information and to weigh the known benefits against the potential risks when prescribing 5-ARIs to their patients.

Healthcare professionals are encouraged to report adverse reactions associated with the use of 5-ARIs to the Vigilance Branch of HSA.

Reference

1. FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer.http://www.fda.gov/Drugs/DrugSafety/ucm258314.htm