E. David Crawford, MD
To determine if 7 months of intermittent degarelix treatment is noninferior to continuous androgen deprivation in maintaining suppression of prostate-specific antigen (PSA) at 14 months.
Patients and Methods:
Patients with rising PSA after prior definitive therapy were randomized to intermittent (degarelix) or continuous (degarelix or leuprolide) treatment arms. All patients initially received 7 months of androgen deprivation. After 7 months, men randomized to intermittent therapy were scheduled to enter a 7-month off-treatment period; degarelix was restarted if PSA levels were >2 ng/mL. Predefined criteria for noninferiority of the primary endpoint, proportion of patients with PSA ≤4 ng/mL, was the lower limit of the 95% CI difference between the intermittent and continuous treatment arms being greater than -12.5% at month 14. PSA, testosterone, and quality-of-life measures were assessed in all patients at multiple time points.
A total of 409 patients were randomized to intermittent (degarelix, n = 177) or continuous (degarelix, n = 50; leuprolide, n = 182) treatment. At month 14, the lower confidence interval limit for intermittent versus continuous treatment was -0.19%; therefore, noninferiority was established. No patients in the intermittent arm had PSA >4 ng/mL at month 14, although 35 patients restarted degarelix before month 14. PSA was >4 ng/mL in 3 (1.6%) patients receiving continuous treatment. In the intermittent arm, 116 (85%) men had testosterone >0.5 ng/mL at a median of 112 days off therapy (95% CI, 112-140). Intermittent treatment was associated with improved sexual drive assessed by the sexual function inventory at month 14 (P = 0.027). The most frequently reported adverse event in all arms was hot flashes. Injection site reactions were more frequent in patients receiving degarelix.
Intermittent degarelix administered as described is noninferior to continuous androgen deprivation in maintaining PSA suppression at month 14. These data indicate that degarelix is a suitable treatment option in men being considered for intermittent androgen ablation.
Androgen deprivation therapy (ADT) is the mainstay of treatment for men with metastatic prostate cancer (PCa) and has been shown to improve survival in combination with radiation therapy in men with high-risk localized disease.1-3
It is also commonly used to treat men with biochemical relapse, especially when classified as high risk. Unlike bilateral orchiectomy, medical castration is reversible and may be used on an intermittent basis. ADT is associated with characteristic side effects including hot flashes; decreased libido, bone mineral density, body mass, muscle mass, and strength; increased body fat, weight; insulin resistance; cardiovascular toxicity; and emotional and cognitive changes.4,5
The potential physical benefits of an intermittent regimen with one or more off-treatment periods are considered to be due to complete or partial testosterone recovery allowing moderation of side effects and improvement of quality of life (QoL).6
Two phase III noninferiority trials of luteinizing hormone-releasing hormone (LHRH) agonists have compared intermittent androgen deprivation (IAD) with continuous androgen deprivation (CAD).7,8
The National Cancer Institute of Canada trial, PR-7 (NCT00003653), enrolled patients with biochemical failure after primary or salvage radiotherapy for localized disease.7 IAD was noninferior to CAD for overall survival (8.8 vs 9.1 years, respectively; HR = 1.02), and scores for hot flashes, desire for sexual activity, and urinary symptoms were significantly improved. Also, men in the CAD arm of PR-7 who achieved nadir testosterone levels <20 ng/mL had an increased time to hormone resistance, demonstrating the importance of achieving low testosterone levels while on treatment.9
The second trial, SWOG 9346 (NCT00002651), compared IAD with CAD for patients diagnosed with metastatic disease (median follow-up, 9.8 years).8
Median survival was 5.8 years and 5.1 years in the CAD and IAD arms, respectively (HR, 1.10). Although survival noninferiority for IAD was inconclusive, IAD was associated with better erectile function and mental health 3 months after discontinuing ADT in the IAD arm compared withthe CAD arm.