ARAMIS Follow-Up: PSA Level, Risk of Radiological Progression in nmCRPC

In the Poster Session dedicated to genitourinary cancers held on Sunday, June 2, 2024, at this year’s American Society of Clinical Oncology Annual Meeting in Chicago, Dr. Alicia Morgans presented a post hoc analysis of the ARAMIS trial of darolutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), which aimed to assess the association between prostate-specific antigen (PSA) kinetics and radiological progression in this population.

Importantly, while PSA is a very useful marker of disease recurrence and progression for patients with localized disease, prior work from Dr. Morgans and colleagues has shown that patients with nmCRPC may have radiographic evidence of disease progression in the absence of PSA progression. In this analysis, the authors evaluated prostate cancer-specific survival among men with nmCRPC who were enrolled in the ARAMIS clinical trial, which established darolutamide as a standard of care for this patient population. Patterns of disease progression were examined both overall and among the subset of patients who achieved PSA <0.2 ng/mL.

In the context of ARAMIS (NCT02200614), patients with nmCRPC were randomized (2:1) to receive either darolutamide (n=955) or placebo (n=554) in addition to androgen deprivation therapy. According to trial protocol, patients underwent PSA determinations and conventional imaging every 16 weeks.

The authors used data from the primary data cutoff of September 2018. They examined prostate cancer-specific survival while accounting from the competing risk of other causes of death. Stratified by treatment group (darolutamide or placebo), they generated state sequence plots to characterize patients according to different potential events: radiological progression, PSA progression, or death. The authors compared radiographical progression between patients who achieved PSA <0.2 ng/mL and those who did not. In the subset who achieved PSA <0.2 ng/mL and experienced radiographical progression, the authors also noted the PSA level at the time of radiological progression.

Darolutamide improved overall survival in ARAMIS, with a hazard ratio (HR) of 0.69 (95% CI, 0.53-0.88). In this patient population, prostate cancer was the leading cause of death in both groups, and receipt of darolutamide was associated with a reduction in prostate cancer-related mortality (6.0% vs 8.2%).

At 12 months postrandomization, PSA progression alone (7.8% vs 35.9%) and PSA and radiological progression (5.4% vs 21.4%) were reduced among patients who received darolutamide. Of interest, among those patients who experienced radiographical progression, those who were receiving darolutamide had lower PSA values at the time of progression (median, 2.4 vs 3.7 ng/mL).

Perhaps not unexpectedly, patients who received darolutamide were much more likely to experience a deep and durable PSA response. Dramatically more patients receiving darolutamide (25.1%) achieved PSA <0.2 ng/mL compared with those receiving placebo (0.5%). Additionally, time to PSA progression was delayed among those receiving darolutamide (median, 33.2 vs 7.3 months; HR, 0.13; 95% CI, 0.11-0.16).

Among patients receiving darolutamide, those who achieved PSA <0.2 ng/mL had a lower risk of radiological progression at 24 months (8.7%) compared with those who had a nadir PSA ≥0.2 ng/mL (33.0%). At 36 months, the cumulative incidence of radiological progression remained at 8.7% for patients receiving darolutamide who achieved PSA <0.2 ng/mL and rose to 50.0% among those with PSA ≥0.2 ng/mL. A small number of patients (11) experienced PSA <0.2 ng/mL and subsequently had radiological progression. At the time of radiological progression, PSA levels were not consistent, ranging from 0.02 to 438.46 ng/mL. Additionally, there was a wide range in time to radiological progression (range, 4-22 months).

Dr. Morgans concluded that, among patients with nmCRPC, darolutamide was associated with deep and durable PSA responses with relatively low rates of PSA progression, with or without radiographical progression. However, a proportion of patients had radiographical progression despite low PSA values. These post hoc results may raise questions about the frequency of conventional imaging for disease progression in patients with nmCRPC.