The availability of CYP17A1 inhibitors (such as abiraterone) and androgen receptor (AR) antagonists (such as enzalutamide) has improved the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC). However, the optimal sequence of agents is unclear and resistance mechanisms are likely to overlap. Now, data from a phase II trial indicate that abiraterone should be administered prior to enzalutamide in this setting.
A total of 202 men with newly diagnosed mCRPC were randomly assigned (1:1) to receive abiraterone plus prednisone, followed by enzalutamide on biochemically confirmed disease progression (group A), or vice versa (group B). Time to second biochemical progression, as indicated by serum prostate-specific antigen (PSA) level, was the primary end point.
At the latest cut-off, similar numbers of patients had crossed over in both arms (72% in group A and 74% in group B). Patients in group A had a significantly longer median time to second progression than those in group B (19.3 months versus 15.2 months, (HR 0.66, 95% CI 0.45–0.97; P = 0.036). This improvement was supported by a superior second-line biochemical response rate (36% versus 4%; P < 0.0001) and improved median time to progression on second-line therapy (3.5 months versus 1.7 months, HR 0.42, 95% CI 0.28–0.65; P < 0.0001), respectively. No significant difference was observed in median time to progression on first-line therapy.
Adverse events were similar to those observed in other trials involving these agents. Hypertension (18% versus 15%) and fatigue (5% versus 3%) in group A versus group B, respectively, were the most frequent grade 3–4 adverse events in response to second-line therapy.
These data demonstrate the superiority of abiraterone followed by enzalutamide for men with newly diagnosed mCRPC; however, how these data relate to the castration-sensitive setting, in which abiraterone is now approved, and to other agents of the same class, remains unclear.
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Khalaf, D. J. et al. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30688-6 (2019)
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Sidaway, P. Sequence of AR inhibitors affects outcome. Nat Rev Clin Oncol 17, 69 (2020). https://doi.org/10.1038/s41571-019-0307-0
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DOI: https://doi.org/10.1038/s41571-019-0307-0