Disease progression patterns and association of prostate-specific antigen level with risk of progression in nonmetastatic castration-resistant prostate cancer

Abstract Background In ARAMIS, darolutamide statistically significantly prolonged metastasis-free survival by 2 years and reduced the risk of death by 31% in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). We report post hoc analyses of ARAMIS evaluating patterns of disease progression overall and by prostate-specific antigen (PSA) response. Methods Patients were randomized 2:1 to darolutamide ( n = 955) or placebo ( n = 554), with androgen-deprivation therapy (ADT). Progression included metastases on conventional imaging, PSA progression based on Prostate Cancer Working Group 2 criteria or any rise in PSA, and pain progression. Radiological progression was compared between patients who reached undetectable PSA < 0.2 ng/ml at any time and those who did not. Results Metastatic progression occurred in 14% of patients receiving darolutamide versus 29% of patients receiving placebo, with a consistent pattern mostly isolated to bone (46%; 39%) or lymph nodes (32%; 40%). At 12 months, fewer patients receiving darolutamide versus placebo had PSA progression alone (7.8% vs. 35.9%) or both PSA and radiological progression (5.4% vs. 21.4%). Radiological progression without PSA progression occurred in 35% of metastatic events in the darolutamide group and 23% of metastatic events in the placebo group. Darolutamide led to deep PSA response (< 0.2 ng/ml) versus placebo (25.1% vs. 0.5%), and patients receiving darolutamide who reached PSA < 0.2 ng/ml experienced less radiological progression than those who did not (24 months: 8.7% vs. 33%; 36 months: 8.7% vs. 50%). Conclusions Darolutamide plus ADT reduced the risk of metastatic progression and improved overall survival versus placebo plus ADT without changing patterns of disease progression through Month 24. Metastasis occurred without PSA progression in approximately 30% of metastatic events overall. Undetectable PSA with darolutamide was associated with reduced radiological progression that was maintained over time. These results highlight the importance of both imaging and PSA monitoring to identify disease progression in patients with nmCRPC.