Hormonal approaches

As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-sensitive or 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. Some forms of hormonal therapy are effective in the management of metastatic hormone-refractory prostate cancer.

Because there are no head-to-head comparisons, there are no trials to help decide which of these agents should be used first or in what sequence they should be used.

Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormonal therapy.[22] The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not shown prognostic significance.[23]

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Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has ranged from 2 to 4 months.[24] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal, as seen in the CLB-9583 trial (NCT00002760).[25][Level of evidence A1] There are conflicting data on whether PSA changes in men undergoing chemotherapy are predictive of survival.[23,26]

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Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from the Eastern Cooperative Oncology Group (ECOG) showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[9] however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.[27]

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Evidence (hormonal approaches for castration-resistant progressive disease with no previous chemotherapy):

Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

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Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

At the second interim analysis, after a median follow-up of 22.2 months, the study was stopped and unblinded because of aggregate efficacy and safety as assessed by the data monitoring committee. At that point, the radiological PFS had reached the prespecified stopping boundary in favor of abiraterone (median PFS, 16.5 months vs. 8.3 months; HR, 0.53; 95% CI, 0.45–0.62; P < .001).

Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

At the fourth (and final) analysis with a median follow-up of 49.2 months (maximum 60 months), 65% of patients in the abiraterone-acetate study arm had died, and 71% of patients in the placebo study arm had died (HR, 0.81; 95% CI, 0.70–0.93; P = .033). Median OS was 34.7 versus 30.3 months.[30][Level of evidence A1]

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Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

Median time to health-related QOL deterioration was long in the abiraterone study arm, as assessed by the Functional Assessment of Cancer Therapy-Prostate Version 4 (FACT-P) total score (12.7 months vs. 8.3 months; HR, 0.78; 95% CI, 0.66-0.92; P = .003) and by the prostate–cancer-specific subscale (11.1 months vs. 5.8 months; HR, 0.70; 95% CI, 0.60–0.83; P < .0001).[31][Level of evidence A3]

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Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[28] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone-refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[29,30][Level of evidence A1] The coprimary end points were radiological PFS and OS. Four sequential analyses were planned.

In addition, patients in the abiraterone study group had statistically significant longer median times to opiate use for pain, initiation of cytotoxic chemotherapy, decline in PS, and PSA progression.[29,31][Levels of evidence A3 and B1]

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Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

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Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

After a median follow-up of 22 months, the study was stopped because of an OS benefit in the enzalutamide study arm (HR, 0.72; 95% CI, 0.6–0.84; P < .001). The proportion of men who had died was 28% versus 35%, and the median OS was 32.4 versus 30.2 months.

Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

Median time until decline in global QOL, measured by the FACT-P score, was 11.3 months in the enzalutamide group and 5.6 months in the placebo group (P < .001). A delayed occurrence of first skeletal-related event requiring clinical intervention was also shown.[32,33][Levels of evidence A3 and B1]

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Enzalutamide, an androgen receptor antagonist, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study (NCT01212991), 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive either enzalutamide (160 mg PO qd) or placebo.[32-34][Levels of evidence A1 and A3]

Grade 3 or worse adverse events were more common in the enzalutamide group (43% vs. 37%), primarily because of differences in hypertension, fatigue, and falls. Because patients receiving enzalutamide were on assigned therapy for an average of 1 year longer than those on placebo, the duration of response was longer in patients receiving enzalutamide, and this difference may have contributed to the increase in adverse events.