Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

102nd Annual Meeting of the American Urological Association

Anaheim, California / May 19-24, 2007

The PCPT (Prostate Cancer Prevention Trial) involved almost 19,000 men 55 years of age or older who had prostate-specific antigen (PSA) values of £3 ng/mL. Patients were randomized to the 5-alpha reductase inhibitor (5ARI) finasteride 5 mg/day or placebo and followed for up to seven years, with regular monitoring by prostate-specific antigen (PSA) and digital rectal exam (DRE). The trial was halted 15 months early when a planned interim analysis revealed a statistically significant reduction in prostate cancer incidence in the active treatment group of 18.4% vs. 24.4% for placebo (P<0.001).

However, PCPT findings also showed a statistically greater number of high-grade cancers (i.e. Gleason score 7 to 10) in men treated with finasteride. Evidence from a variety of sources has pointed to two possibilities: an artifact resulting from a biopsy-related sampling error; or finasteride-induced improvement in the performance characteristics of PSA for prostate cancer detection.

“We know that finasteride increases the sensitivity of PSA and DRE for detecting prostate cancer, and we know it improves prostate biopsy detection of high-grade cancer,” stated Dr. Ian M. Thompson, Chair of Urology, University of Texas Health Science Center, San Antonio (UTHSA) and PCPT principal investigator. The assertions are supported by two recent publications based on PCPT data (Thompson et al. J Natl Cancer Inst 2006;98(16):1128-33, Thompson et al. J Urol 2007;177(5):1749-52).

Prostate Volume and Biopsy

In the PCPT, finasteride led to a significant reduction in prostate volume and in the process improved the ability of biopsy to detect and grade cancer. If high-grade cancer is present, a smaller gland increases the likelihood that the cancer will be detected and more accurately staged, Dr. Thompson noted. In fact, biopsies detected 70% of high-grade cancers in the active treatment group compared to 50% in the placebo group (P=0.01). A recent Canadian study corroborated the PCPT results, showing that the risk of missing high-grade prostate cancer on biopsy increases with prostate volume (Kulkarni et al. J Urol 2006;175(2):505-9).

“The conclusion of this observation is that there appears to be a differential detection of high-grade disease in a subject receiving finasteride, most likely due to a greater degree of sampling of the gland due to its smaller size,” Dr. Thompson told delegates.

He cited a study published in the June issue of the Journal of Urology indicating that finasteride also appears to reduce the likelihood of high-grade prostatic intraepithelial neoplasia, with or without concomitant cancer. As Dr. Thompson pointed out, a lower incidence of these neoplasias means fewer biopsies.

Dr. Thompson reviewed additional findings that exonerate finasteride of inducing high-grade cancer. If the compound induced high-grade cancer, the number of cases would increase with duration of treatment. That did not occur in the PCPT. In fact, the entire difference between the two treatment groups occurred during the first year of follow-up.

An especially insightful observation involved the dissociation between biopsy and prostatectomy findings. Among placebo patients, pathologic evaluation of prostatectomy specimens led to upgrading of cancers about 25% more often than in the finasteride group. In contrast, almost 20% of prostatectomy specimens from finasteride patients were downgraded from biopsy grading compared to 12.5% of specimens from placebo patients.

Trials in Progress

The examination of the 5ARIs’ ability to reduce prostate cancer risk is continuing in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. The trial involves 8200 men 50 years of age and over who have baseline PSA values of 2.5 to 10 ng/mL and no evidence of prostate cancer at enrolment, as confirmed by biopsy within six months of randomization (Gomella LG. Curr Opin Urol 2005;15(1):29-32). Follow-up will continue for four years after assignment to the 5ARI dutasteride or placebo. The primary outcome measure is prostate cancer incidence.

Another ongoing study is exploring the 5ARIs’ possible role in the management of patients with low-risk prostate cancer entered into active surveillance or watchful waiting. Investigators in the REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer) trial hope to determine whether a 5ARI can shrink prostate cancers and reduce PSA levels and, in the process, prevent or delay the need for aggressive treatment.

Prognostic Value of the Prostate Cancer Risk Calculator

Physicians can readily apply the PCPT findings to clinical practice by making use of a prostate cancer risk calculator derived from PCPT data, also discussed here at the AUA (http://www.compass.fhcrc.org/edrnnci/bin/calculator/).

In one study, Dr. Thompson and colleagues applied the risk calculator to a more heterogenous population of men to evaluate its utility. The study involved 446 of the 3488 participants in the SABOR (San Antonio Center for Biomarkers of Risk for Prostate Cancer). In comparison to the PCPT study population, SABOR participants are younger, more ethnically diverse, and have a higher rate of positive family history.

Analysis of the SABOR data focused on men who had undergone prostate biopsy and had a PSA test and DRE prior to the biopsy, explained Dr. Dipen Parekh, Assistant Professor of Urology, UTHSA. The biopsies led to prostate cancer diagnoses in 148 cases.

He and colleagues examined associations between prostate cancer risk and PSA, DRE, age, family history, race and ethnicity and compared the findings to the score derived from the PCPT risk calculator. The comparison showed a strong correlation between SABOR cancer rates and increasing PCPT risk, as rates increased from 15.7% to 100% as the risk calculator scores increased from <25% to >75%.

“The PCPT risk calculator incorporates the best panel of risk factors currently available into a tool that is readily accessible to all practitioners,” stated Dr. Parekh. “The results of this study have proven that the risk calculator is valid in a more diverse population than the original PCPT population.”

Two other validation studies provided additional evidence of the risk calculator’s applicability to clinical practice. One study involved 1108 men who underwent prostate biopsy and had complete clinical data. Analysis of receiver operator characteristics showed that the PCPT risk calculator was associated with an area under the curve (AUC) of 0.67, which was significantly better than the 0.62 AUC for PSA (P=0.0002). For predicting high-grade cancer, the risk calculator had an AUC of 0.74 vs. 0.71 for PSA (P=0.024), reported Dr. David Hernandez, Johns Hopkins University, Baltimore, Maryland.

A second multicentre evaluation yielded similar findings from an analysis of data on 4672 men who underwent prostate biopsies, 1501 of which resulted in prostate cancer diagnoses, including 224 cases of high-grade cancer. The AUC for predicting cancer of any grade was 0.66 for the risk calculator and 0.64 for PSA alone (P=0.01), according to Dr. Misop Han, Johns Hopkins University. The AUC for predicting high-grade cancer was 0.63 for the PCPT risk calculator and 0.57 for PSA alone (P<0.001).

Benign Prostatic Hyperplasia and Lower Urinary Tract Syndrome

Prior to the recent investigations into prostate cancer prevention, other studies showed that 5ARIs effectively relieve benign prostatic hyperplasia (BPH) symptoms and reduce the risk of BPH progression to invasive treatment and urinary retention (McConnell et al. N Engl J Med 1998;338(9):557-63, Roehrborn et al. Urology 2002;60(3):434-41, McConnell et al. N Engl J Med 2003;349(25):2387-98, Debruyne et al. Eur Urol 2004;46(4):488-94).

Dr. Roger Kirby, Professor of Urology, St. George’s Hospital, London, UK, summarized the current status of 5ARIs for treatment of BPH as reflected in clinical experience and clinical research. The agents “improve symptoms and enhance urinary flow. They work most effectively when prostate volume exceeds 30 cc and PSA is >1.4 ng/mL. 5ARIs reduce the incidence of acute urinary retention and the need for invasive therapy by around 50%. The agents induce reversible sexual dysfunction in 3% to 5% of patients and gynecomastia in 1%.”

The safety and efficacy of 5ARIs for treatment of BPH/lower urinary tract symptoms (LUTS) provide a measure of reassurance for clinical practitioners who have seen no decline in the population of men seeking treatment for prostate enlargement and urinary symptoms. An epidemiologic study reported by Dr. Donald Naslund, University of Maryland, Baltimore, showed that 42% of men ³50 years of age have LUTS, as defined by an International Prostate Symptom Scale (IPSS) score >7. Additionally, two-thirds of the men had a pathologically enlarged prostate by DRE or PSA, and 30% had IPSS scores >7 plus prostate enlargement by DRE or PSA level. However, only a third of the men with BPH/LUTS said they intended to discuss the urinary symptoms with their primary care providers. Dr. Naslund stressed, “It is incumbent on physicians to initiate the conversation about urinary symptoms and prostate enlargement, so that patients who might need treatment will get it.”

The importance of initiating discussions with men about BPH/LUTS was underscored in another presentation showing that health-related QOL (HRQOL) is the best predictor of BPH progression to invasive treatment. The findings emerged from an analysis of data in the BPH Registry, a multicentre, longitudinal, observational disease registry that prospectively collects demographic, clinical and HRQOL data on men who seek treatment for BPH/LUTS, explained Dr. Claus Roehrborn, Chair of Urology, Southwestern Medical Center, Dallas, Texas.

Evaluation of data on 3854 patients included in the registry revealed that 120 (3.1%) had BPH-related surgery an average of 223 days after presentation. Separate analysis of patients who progressed to surgery provided additional confirmation of finasteride’s ability to minimize the risk of progression. Patients whose BPH was managed by alpha-blockers (selective or nonselective) had a surgery rate of 4.6% to 4.7%, compared to 1.4% for men treated with a 5ARI (P=0.0142). Somewhat surprisingly, men receiving combination therapy (shown to be most effective for preventing progression in recent studies) had a surgery rate of 6.6%. In a multivariate analysis of potential predictors of progression to surgery showed that only a higher BPH Impact Index (reflecting worse HRQOL) remained statistically significant.

As reported by Dr. Theodore Johnson, Emory University, Atlanta, Georgia, finasteride, the alpha-blocker doxazosin and the combination all demonstrated some degree of efficacy for managing nocturia, a particularly troubling symptom of BPH/LUTS. The finding came from a secondary analysis of one- and four-year data on 2583 men who participated in the MTOPS (Medical Therapy of Prostatic Symptoms) study (McConnell et al. N Engl J Med 2003;349(25):2387-98). At one and four years, men treated with doxazosin or combination doxazosin/finasteride experienced significant improvement in nocturia (P<0.05). Among men ³70 years of age, all three active treatment strategies resulted in significantly fewer nocturia episodes compared to placebo (P<0.05).

Although the MTOPS trial demonstrated the efficacy of combination medical therapy to reduce the risk of BPH progression, the results also raised the question of whether patients can be transitioned from successful combination therapy to monotherapy. A multicentre Canadian study provided an affirmative answer to the question, at least with respect to finasteride.

Dr. Jack Barkin, University of Toronto, and colleagues examined the safety and efficacy of monotherapy in patients initially treated with combination therapy. The study involved 124 men who had an IPSS >12 and prostatic enlargement at initial presentation. All of the men had received combination therapy for nine months before being switched for finasteride for an additional nine months of treatment. The principal outcome measure was therapeutic equivalence, defined as a change of <2 points on the IPSS after the switch to monotherapy. After nine months of combination therapy, the mean IPSS score declined from 19.5 to 11.9 (P=0.0001). At the end of nine months of finasteride monotherapy, mean IPSS score was 11.5.

“This open-label, non-randomized study demonstrated that, in patients with moderate to severe symptoms of BPH, finasteride therapy alone for nine months maintained the urinary symptoms control and QOL improvement that had been achieved after an initial nine months of combination therapy with finasteride and an alpha-blocker,” Dr. Barkin and colleagues concluded.

Summary

Ongoing analysis of data from the PCPT has confirmed that the 5ARI finasteride reduces the risk of prostate cancer in men who are free of cancer at the start of therapy. Multiple lines of evidence have provided reassurance that a higher rate of high-grade cancer observed in PCPT patients treated with finasteride occurred as a result of its favourable effects on the performance characteristics of PSA testing and as a result of improved sampling on biopsy due to its shrinking of the prostate. New data also provided additional evidence of its ability to reduce symptoms of BPH/LUTS and to minimize the risk of progression to invasive treatment. It also has demonstrated safety and efficacy for transitioning BPH/LUTS patients from combination medical therapy to monotherapy.

According to Dr. Thompson, the goal of finasteride therapy extends beyond prevention of prostate cancer mortality, which in itself would be a remarkable achievement. However, he added, the ultimate goal should be to reduce the overall burden of the disease. Noting that 92% of men with prostate cancer receive treatment, Dr. Thompson said treatment “permanently changes a man’s life. Urinary, bowel and sexual dysfunction affect many patients. Physicians consistently underestimate the impact of these problems.” Early detection, successful treatment, and salvage of recurrent disease are certainly worthy of societal resources, he concluded, but “as for me, I would rather never have [prostate cancer] in the first place.”