Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.15 In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.15
Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.16 Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.
Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).
Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.17 The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.18 Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.19
Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.20 Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.21 Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.22,23
The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).24 Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.25 Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.
