When men with advanced prostate cancer develop radiographic progression while taking enzalutamide, they frequently show little to no rise in prostate-specific antigen (PSA), according to a post hoc analysis of two clinical trials.

Researchers found that among patients taking enzalutamide plus androgen deprivation therapy (ADT), about half of those who developed radiographic progression did so without a significant increase in PSA. And roughly 1 in 4 had no PSA rise at all.

The findings, published in the Journal of Clinical Oncology, highlight the limitations of PSA monitoring alone in these patients. And they support a shift toward imaging surveillance that’s already underway, experts said.

“The findings from this post hoc analysis will impact the guidance that’s provided for the frequency of imaging for patients with prostate cancer who are receiving treatment with androgen receptor pathway inhibitors [ARPI],” Kevin Courtney, MD, PhD, director of genitourinary medical oncology at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, told Medscape Medical News.

Courtney, who was not involved in the study, noted that historically, imaging surveillance schedules have largely been guided by factors like PSA velocity and disease risk.

However, that paradigm changes when patients receive ADT plus an ARPI such as enzalutamide because these can lead to androgen-independent resistance. Consequently, disease progression may not trigger a rise in PSA.

Radiographic progression without a corresponding PSA change has been reported, including in some trials evaluating enzalutamide plus ADT. For the new study, researchers led by Andrew J. Armstrong, MD, of Duke University in Durham, North Carolina, sought to better define the prevalence and clinical impact of the phenomenon.

The researchers conducted a post hoc analysis of data from two randomized, phase 3 trials: ARCHES, which involved 1150 patients with metastatic hormone-sensitive prostate cancer who received enzalutamide plus ADT or placebo plus ADT; and PROSPER, which included 1401 patients with nonmetastatic castration-resistant prostate cancer who were on ADT and randomly assigned to either enzalutamide or placebo.

They found that in ARCHES, radiographic progression without PSA rise was far more common among patients on enzalutamide than those on ADT alone (25.3% vs 7.4%). Radiographic progression without meeting standard PSA progression criteria was also notably different between groups (62.0% vs 38.3%).

The PROSPER data echoed these findings. Radiographic progression without PSA rise was far more common among enzalutamide-treated patients (21.9% vs 3.6%), as was radiographic progression without meeting standard PSA progression criteria (51.3% vs 18.8%).

In both trials, liver metastases were more common among patients treated with enzalutamide who developed radiographic progression. Radiographic progression, with or without a change in PSA, was associated with worse overall survival.

“After treatment with enzalutamide, PSA levels decline due to potent androgen receptor blockade and cell death,” Armstrong and his colleagues wrote. “Although PSA decline is prognostic and associated with improved long-term outcomes, detection of radiographic progression could be delayed if imaging studies are only guided by PSA levels.”

The new data, they added, argue for regular bone and soft tissue imaging, at least during the first 2 years of therapy.

Jon Chatzkel, MD, medical oncologist at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, agreed that the findings have practice implications.

“Despite the inherent limitations of post hoc analyses,” Chatzkel said, “these findings nonetheless have the potential to impact clinical practice regarding imaging frequency in patients with prostate cancer who are on an ARPI.”

This move toward more frequent imaging is already happening, supported by recent guidance from the Prostate Cancer Working Group 4 (PCWG4), Courtney said.

Specifically, the PCWG4 emphasizes that imaging intervals should be tailored to disease state and clinical context. For patients with androgen pathway modulator-sensitive or naive disease, including those with biochemical recurrence with or without metastases, the group proposes conventional imaging with bone scan and CT at baseline, 3 months, and 6 months, followed by every 6 months thereafter. With prostate-specific membrane antigen (PSMA) PET, the guidance suggests imaging at baseline, 3 months, and 6 months, with additional scans at 12 and 18 months.

The data from this new analysis, Courtney said, should make it even easier for physicians to perform conventional imaging. When it comes to PSMA PET, he noted, “We’ll have to see how payers and Medicaid respond to the review of these data.”

The study was supported by Pfizer and Astellas Pharma. The investigators disclosed having additional relationships with Bayer, Janssen, Novartis, and others. Courtney and Chatzkel reported having no relevant conflicts of interest.