AUA: New Therapies Show Promise for BPH

By Charles Bankhead
ORLANDO, 28 may 2008 -- Two new therapeutic strategies for benign prostatic hyperplasia (BPH) -- one oral, one injectable -- showed promise in clinical trials, investigators said here.
The vitamin D agonist elocalcitol significantly slowed prostate growth and improved urinary flow in a placebo-controlled dose-finding study reported at the American Urological Association meeting.
A second study found that a single intraprostatic injection of a PSA-activated protoxin significantly reduced prostate symptoms and volume in a small phase 1 clinical evaluation.
Elocalcitol is a nonhypercalcemic vitamin D agonist that demonstrated anti-inflammatory and antiproliferative activity in preclinical studies, said Francesco Montorsi, M.D., of the Universita Vita Salute San Raffaele in Milan, Italy. Preliminary clinical studies showed that elocalcitol arrests prostate growth and improves bladder function.
Clinical investigation continued in a dose-finding study involving 540 men with symptomatic BPH.
The patients were randomized to placebo or to one of three active therapies: elocalcitol 75 or 150 mcg or elocalcitol 150 mcg plus the alpha blocker tamsulosin (Flomax) at a dose of 0.4 mg.
Treatment continued for six months, and the primary endpoint was the percentage change in total prostate volume from baseline.
All three active-therapy groups did significantly better compared with placebo, which had a mean increase in prostate volume of 3.52%.
Prostate volume increased by 1.52% with the 75 mcg dose of elocalcitol (P<0.0135), 0.54% with 150 mcg of elocalcitol (PP=0.0059).
"The rate of prostate growth in the placebo group was in line with published literature," Dr. Montorsi said. "The reduced rate of growth with elocalcitol shows that the drug can arrest prostate growth."
Prostate symptoms improved by five to six points on the International Prostate Symptom Scale and did not differ between groups. Similarly, maximum urinary flow (Qmax) improved by about 1 to 2 mL/sec in all four groups.
"The results seem to be comparable to those historically obtained with the 'gold standard' alpha-blockers," said Dr. Montorsi.
In a subgroup analysis of men with IPSS scores ≥12 and at least three urgency episodes daily at baseline, the 150 mcg dose of elocalcitol led to significant improvement (P<0.01) compared with placebo, as did combination therapy (P<0.04).
Adverse events occurred less frequently with elocalcitol monotherapy compared with placebo and slightly more often with the combination, but the differences were not significant.
In particular, elocalcitol did not adversely affect sexual function compared with placebo.
Explaining the second strategy, investigators in Canada and at Johns Hopkins presented data from 15 patients treated with PRX302, a modified bacterial protoxin injected into the prostate.
The modified protoxin (proaerolysin) is activated by PSA, resulting in the release of C-terminal inhibitory peptide and generation of active toxin, said Peter J. Pommerville, M.D., of Can-Med Clinical Research in Victoria, British Columbia.
"We believe the activated toxin bores small holes into cell membranes, allowing the cell contents to leak out and promoting apoptosis," Dr. Pommerville said in an interview. "The end result is a reduction in prostate volume."
In the phase I study, three patients each received one of five doses of PRX302. Using transrectal ultrasound guidance, investigators injected the protoxin transperineally into both prostatic lobes. Additionally, three or four deposits per injection were made in the transition zone along the urethra.
The baseline prostate volume averaged 45.3 cm3 and decreased to 37.7 cm3 at 90 days (P<0.01).
IPSS score decreased from a baseline mean of 19.1 to 9.4 at 90 days (P=0.015).
Quality-of-life score improved from a mean of 4.3 at baseline to 1.8 at 90 days (P<0.01).
"We hypothesize that the reduction in prostate mass reduces the pressure on the urethra, leading to a reduction in prostate symptoms," said Dr. Pommerville.
The protoxin was well tolerated; no grade 3-4 adverse events occurred during the study, he added. The most common adverse event was urinary frequency.
Dr. Montorsi disclosed relationships with GlaxoSmithKline, Pfizer, Bayer, Eli Lilly, Pierre Fabre, and AMS. Dr. Pommerville disclosed that he is an investigator for Protox Therapeutics.
Primary source: Journal of UrologySource reference:Montorsi F, et al "Elocalcitol in the treatment of BPH: a multicenter, randomized, placebo-controlled phase IIb clinical trial" J Urol 2008; 179(suppl): 700; Abstract 2035. Additional source: Journal of UrologySource reference: Pommerville PJ, et al "A PSA-activated protoxin (PRX302) administered transperineally to men with symptomatic benign prostatic hyperplasia is well tolerated and exhibits signs of activity" J Urol 2008; 179(suppl): 673; Abstract 1961.