Prostate Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Recurrent Prostate Cancer Treatment
Hormonal Therapy for Recurring Disease
Intermittent versus continuous androgen suppression therapy
The majority of men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation therapy (IAD) can be used as an alternative to continuous androgen deprivation (CAD) therapy (ADT) in an attempt to improve quality of life and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.
- This important clinical question was addressed in a "noninferiority" designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/ml, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[Levels of evidence: 1iiA, 1iiB, 1iiC]
- The ADT arm consisted of 8-month treatment cycles with an LH-RH agonist (combined with a nonsteroidal antiandrogen for at least the first 4 weeks) that was reinstituted if the PSA level exceeded 10 ng/ml. The study was powered to detect (with 95% confidence) an 8% lower OS rate in the IAD group compared with the CAD group at 7 years.
- After a median follow-up of 6.9 years (maximum follow-up 11.2 years), OS in the two groups was nearly identical, and the study was stopped (median survival 8.8 vs. 9.1 years; hazard ratio [HR]death of 1.02; 95% confidence interval [CI], 0.86–1.21). This fulfilled the prospective criterion of noninferiority.
- In a retrospective analysis, prostate cancer-specific mortality was also similar in the two arms (HR, 1.18; 95% CI, 0.90–1.55; P = 0.24). In addition, IAD was statistically significantly better than CAD in several quality-of-life domains, such as hot flashes, desire for sexual activity, and urinary symptoms. Patients on the IAD study arm received a median of 15.4 months of treatment versus 43.9 months on the CAD arm.
- The study does not address the unanswered question about whether the initiation of any ADT for an elevated PSA after initial local therapy extends survival compared with delay until clinically symptomatic progression. Of note, 59% of all deaths were unrelated to prostate cancer, and only 14% of all patients died of prostate cancer.
As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy.
Evidence (hormonal approaches):
- Abiraterone inhibits androgen biosynthesis by blocking cytochrome P450 c17 (CYP17). Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) orally once a day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg) orally twice a day.[Level of evidence; 1iA]
- After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. The final report of the trial was published after a median follow-up of 20.2 months.
- Median OS was 15.8 months in the abiraterone group versus 11.2 months in the placebo group (HRdeath of 0.74; 95% CI, 0.64–0.86; P < .0001).
- Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, and hypertension.
- Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase survival in patients with progressive prostate cancer who received prior androgen deprivation therapy as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg orally per day) versus placebo.[Levels of evidence; 1iA, 1iC]
- After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found in the enzalutamide study group (median OS, 18.4 months; 95% CI, 17.3 to not yet reached vs. 13.6 months; 95% CI, 11.3–15.8; HRdeath of 0.63; 95% CI, 0.53–0.75; P < .001). In addition, quality of life, measured by the FACT-P questionnaire, was superior in the enzalutamide arm.
A seizure was reported in five of the 800 men in the enzalutamide study group, versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous lidocaine, and one seizure was not witnessed.