PRESIDENTIAL Study: Evaluation of Enzalutamide in Combination With Chemotherapy in Patients With Metastatic Prostate Cancer

The PRESIDE study was conducted to evaluate the continued efficacy of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after initial docetaxel therapy. The aim was to determine whether maintaining enzalutamide in combination with subsequent chemotherapy could offer additional benefits compared to chemotherapy alone.

The study design was multicenter, randomized, and double-blind. Patients were initially treated with enzalutamide monotherapy until disease progression. After this period, participants were randomized to receive enzalutamide plus docetaxel and prednisone or docetaxel and prednisone alone. The primary outcome analyzed was radiographic progression-free survival (rPFS), while overall survival (OS) and response rate were included as secondary outcomes.

The results of the PRESIDENTIAL study, conducted with 271 patients with metastatic castration-resistant prostate cancer (mCRPC), revealed important information about the detection of ctDNA (circulating tumor DNA) and its association with the efficacy of treatment with docetaxel and enzalutamide. Radiographic progression-free survival (rPFS) demonstrated that patients with positive ctDNA at baseline had a significantly shorter survival compared to ctDNA-negative patients (8.1 months versus 10.8 months, p = 0.004). In addition, the analysis of resistance biomarkers revealed that patients with mutations in the AR-V7 gene and plasma RA gain did not benefit from the continuation of enzalutamide, evidencing the importance of biomarker evaluation to optimize therapeutic decisions. The response rate to treatment was lower in patients with resistance biomarkers, and overall survival (OS) did not show significant difference between treatment arms.

Regarding safety data, treatment was generally well tolerated, with grade 1 to 2 adverse events being predominant. Toxicity was not significantly different between the enzalutamide and placebo treatment groups, except for adverse effects related to docetaxel use. Sequential collection of blood samples revealed that ctDNA levels decreased significantly during treatment (26.1% at C2D1 compared to 55.1% at baseline, p < 0.001), suggesting that ctDNA monitoring may be useful to assess response to treatment. The findings of the PRESIDE study reinforce the potential for maintaining enzalutamide in patients with mCRCP who progress after docetaxel use.

Although the combination demonstrated prolonged rPFS and higher response rate, the impact on overall survival remains uncertain. Thus, the clinical decision on the continuity of treatment should consider not only the benefits in the progression of the disease, but also the associated toxicity profile.

These results contribute to the understanding of the role of enzalutamide in the therapeutic sequence of mCPRC, providing subsidies for the personalization of treatment strategies and highlighting the importance of further studies to evaluate the impact of combination therapy on the overall survival of patients.