PCPT

Published

Thompson IM, et al. "The influence of finasteride on the development of prostate cancer". The New England Journal of Medicine. 2003. 349(3):215-224.
PubMed • Full text • PDF

Clinical Question

Does daily finasteride therapy reduce prostate cancer development when compared to placebo?

Bottom Line

Finasteride reduces the incidence of prostate cancer but causes sexual side effects and increases the incidence of high-grade prostate cancer when compared to placebo for primary prevention.

Major Points

Androgens promote the development of prostate cancer. Inhibiting the synthesis of the potent androgen dihydrotestosterone (DHT) with the 5α reductase inhibitor finasteride may therefore reduce the risk of prostate cancer. A large, randomized clinical trial had not been undertaken, however.

The 2003 Prostate Cancer Prevention Trial (PCPT) randomized 18,882 men age ≥55 years to finasteride or placebo for seven years. The trial was stopped early by the safety monitoring board. While finasteride was associated with lower rates of all-types of prostate cancer (18.4% vs. 24.4%) it was associated with higher rates of high-grade (Gleason ≥7) prostate cancer (6.4% vs. 5.1%) as well as increased sexual side effects. There was no difference in mortality between the two groups. Results were similar at 10 years of follow-up. The authors note that the overall incidence of prostate cancer detection rate of 24.4% raises concern for overdiagnosis of the disease since the expected rate based upon the population studied was 16.7%.

Multiple theories have attempted to explain the paradoxical increase in high-grade prostate cancer. Modifications in androgen levels may have altered the histologic appearance of cells without altering their overall pathogenicity. Unintentional reduction of the estrogen receptor β stimulation may have promoted propagation of more poorly-differentiated cells. These arguments are supported by the observation that increased risk of high-grade malignancy was in the first year and that the relative risk did not increase over time.

The smaller and shorter-duration REDUCE trial (2010) compared the 5α reductase inhibitor dutasteride to placebo and found that the medication was associated with a 22.8% reduction in all grades of prostate cancer at 4 years. However, in years 3 and 4, there was a statistically significant increase in Gleason 8-10 disease in the dutasteride group. Given these data, the FDA has not granted either 5α reductase inhibitor the indication of prostate cancer prophylaxis.

Guidelines

ASCO/AUA (2008, adapted)

• Informed conversation with patients considering therapy with 5α reductase inhibitors, including that the therapy:
  • Reduces incidence of prostate cancer but not to zero
  • Increases rate of high-grade cancer in the PCPT trial
  • Effects of treatment beyond 7 years is not known
  • May cause reversible sexual side effects
  • Improves in lower urinary tract symptoms

Design

• Prospective, double-blind, placebo-controlled trial
• N=18,882
  • Finasteride Group (n=9,423)
  • Placebo Group (n=9,459)
• Setting: 221 study sites in the US
• Enrollment: 1994-1997
• Goal follow-up: 7 years (stopped 15 months early, >80% of patients had 7 years of follow-up)
• Analysis: Intention-to-treat
• Primary outcome: Prostate cancer

Population

Inclusion Criteria

• Men age ≥55 years
• Normal DRE
• "No clinically significant coexisting conditions"
• AUA symptom score <20

Exclusion Criteria

• Post-run in PSA >3.0 ng/mL
• Poor adherence to run-in or development of "clinically significant" side effects

Baseline Characteristics

Not presented by the authors.

Interventions

• Three-month run-in with daily placebo, those with PSA ≤3 ng/mL, good adherence, and no clinically significant side effects were randomized to a group:
  • Finasteride 5 mg PO qday
  • Placebo daily
• Both groups underwent annual DREs and PSA
  • The PSA level was weighted for those in the finasteride group (2x for first 3 years, 2.3x thereafter) as to ensure blinding
  • A prostate biopsy was recommended for an abnormal DRE or PSA >4.0 ng/mL
• At 7 years, all participants without diagnosis of prostate cancer were offered prostate biopsies

Outcomes

Comparisons are finasteride vs. placebo. RRR is relative risk reduction, RR is relative risk.

Primary Outcome

Any prostate cancer within 7 years and 90 days of randomization

18.4% vs. 24.4% (RRR 24.8%; 95% CI 18.6-30.6%; P<0.001)

Secondary Outcomes

Gleason ≥7

6.4% vs. 5.1% (RR 1.67; 95% CI 1.07-1.50; P=0.005)

Rate of tumors graded Gleason ≥7:

37.0% vs. 22.2%

"For-cause" biopsies: 47.8% vs. 29.4% (RR 1.62; 95% CI 1.37-1.93; P<0.001)

Rate in men undergoing this biopsy: 11.5% vs. 7.7% (RR 1.50; 95% CI 1.22-1.84; P<0.001)

End-of-study biopsies: 25.3% vs. 15.8%

Prostate cancer mortality

5 vs. 5 participants

Additional Analyses

Prostate cancer or end-of-study biopsy

59.6% vs. 63.0% (P<0.001)

Biopsies recommended because of abnormal DRE or elevated PSA

22.5% vs. 24.8% (P<0.001)

Subgroup Analysis

A similar relative risk reduction for the primary outcome was preserved for subgroup analysis by age, race, family history of prostate cancer, and PSA on entry.

Adverse Events

Sexual or endocrine

Reduced ejaculate volume: 60.4% vs. 47.3% (P<0.001)

ED: 67.4% vs. 61.5% (P<0.001)

Libido loss: 65.4% vs. 59.6% (P<0.001)

Gynecomastia: 4.5% vs. 2.8% (P<0.001)

Breast cancer : 1 vs. 1 individual

GU

BPH: 5.2% vs. 8.7% (P<0.001)

Increase urinary urgency/frequency: 12.9% vs. 15.6% (P<0.001)

UI: 1.9% vs. 2.2%

Urinary retention: 4.2% vs. 6.3% (P<0.001)

TURP performed: 1.0% vs. 1.9% (P<0.001)

Prostatitis: 4.4% vs. 6.1% (P<0.001)

UTI: 1.0% vs. 1.3% (P<0.001)

Temporary discontinuation of treatment at some point

36.8% vs. 28.9% (P<0.001)

Criticisms

• Unclear if increased Gleason grade is due to treatment effect whereby the appearance of intermediate-grade tumor cells is worsened on histologic review
• The use of a weighted PSA value in the finasteride group to trigger biopsy resulted in fewer biopsies performed and, perhaps, reduction in detection of prostate cancers rather than reduction in prostate cancers
• The majority of small prostate cancers occur in the lateral portion of the peripheral zone, finasteride causes this area to move anteriorly and out of the path of usual biopsies since the medication reduces the size of the transitional zone. This may have reduced detection of the low- to medium-grade tumors that subsequently progressed to a higher grade. Use of prostate ultrasound in performing these biopsies may have improved this.
• Use of end-of-study prostate biopsies is not reflective of clinical practice and may have increased detection of latent cancers that were not as clinically significant as those detected from biopsy triggered by elevated PSA or abnormal DRE
• Finasteride may increase the development of breast cancer in men

Funding

• NCI Public Health Service grants
• Finasteride and placebo provided by Merck (manufacturer of Proscar and Propecia, the trade names of finasteride)