Pattern of metastatic spread impacts whether enzalutamide plus ADT improves PFS in prostate cancer

"Here we show that there are clear benefits in delaying radiographic progression or death, [PSA] progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” says Andrew Armstrong, MD.

Treating men with metastatic hormone-sensitive prostate cancer with enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) can improve progression-free survival (PFS) if patients have bone and/or lymph node metastases. The combination, however, appears to be less effective among men who have visceral patterns of spread, according to a study published in the Journal of Urology.1

The pattern of metastatic spread in prostate cancer has clear prognostic implications. What has not been understood is how a pattern of spread impacts potential benefits of adding more potent androgen receptor inhibition to ADT, according to study author Andrew Armstrong, MD, professor of medicine, associate professor in pharmacology and cancer biology, and professor in surgery at Duke University School of Medicine, in Durham, North Carolina.

“Here we show that there are clear benefits in delaying radiographic progression or death, prostate-specific antigen (PSA) progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” Armstrong said. “Men with organ (visceral, such as lung and liver sites) metastases were found to have a poor prognosis, and this small subgroup did not clearly have a delay in radiographic progression with the addition of enzalutamide. Much of this was driven by the poor outcomes of men with liver metastases, whereas men with lung metastases only had a more favorable prognosis and had improved outcomes with enzalutamide/ADT.”

The international group of investigators conducted a post hoc analysis of men with metastatic hormone-sensitive prostate cancer from the phase 3 ARCHES trial (NCT02677896). Investigators randomized 1146 men with metastatic hormone-sensitive prostate cancer to 160 mg/day of enzalutamide plus ADT or placebo and ADT, with the primary end point being radiographic PFS. There were 513 patients with bone metastases only, making up the largest study subgroup. Among the other subgroups, 351 men had bone and lymph node metastases, 154 had lymph node metastases only, and 128 had visceral plus or minus bone or lymph node metastases.

The study results found benefits of enzalutamide and ADT in men with node only and bone plus or minus lymph node metastases and lung metastases, regardless of disease volume.

According to Armstrong, the limited benefits in men with liver metastases suggests that it may be less androgen receptor-dependent, which calls for new strategies to understand this pattern of spread at the molecular level to reduce death and negative experiences from prostate cancer.

“Liver metastases were already known to be associated with a poor prognosis in metastatic castrate-resistant prostate cancer, but our data add to this importance in earlier disease settings,” he said.

For now, urologists and oncologists should consider a liver biopsy to evaluate for neuroendocrine or small cell prostate cancer as per National Comprehensive Cancer Network and American Urological Association guidelines, according to Armstrong.

“Such men are more likely to benefit from docetaxel and ADT in this setting, given the results of the CHAARTED [NCT00309985] and STAMPEDE trials [NCT00268476],” he said.

Radiographic PFS is a clinically relevant end point that urologists and other physicians use to make treatment decisions that impact patients’ lives in practice, Armstrong said.

There are major treatment implications when a patient with metastatic hormone-sensitive prostate cancer progresses to metastatic castration-resistant prostate cancer, requiring changes to strategies, given the abundance of approved agents in the metastatic castration-resistant prostate cancer setting. According to Armstrong, with the profound improvements in radiographic PFS observed in ARCHES, the FDA approved enzalutamide in the metastatic hormone-sensitive prostate cancer setting.

“Patients were offered cross-over and open-label access to enzalutamide,” he said. “Enzalutamide is known to improve survival in castrate-resistant prostate cancer patients already, and continuing this study to a survival primary end point was not reasonable given the results of the ENZAMET trial [NCT02446405], which demonstrated improved survival with enzalutamide in this setting.”

According to Armstrong, There are downsides to adding the androgen receptor inhibitor to treatment. Enzalutamide adds adverse effects to ADT alone, including fatigue, high blood pressure, loss of bone density, fracture risks, muscle loss, fall risk, and hot flushes. Some men experience cognitive issues with fatigue. Providers can help patients reduce these adverse effects through attention to exercise, bone health, cardiovascular risk factors, and blood pressure monitoring.

The work to find optimal treatments for these patients is far from over.

“Although enzalutamide, abiraterone, and apalutamide each extends life in men with metastatic hormone-sensitive prostate cancer, these patients still progress after several years of treatment, and new therapies are needed,” Armstrong said. “Men with liver metastases progress the fastest, and this group represents the largest unmet medical need where research is needed to understand how prostate cancers favor the liver microenvironment and how we can improve survival in this setting and prevent liver metastases.”

Future studies, he said, will examine whether enzalutamide and ADT after completion of docetaxel and ADT in these patients with poor-prognosis, visceral metastatic hormone-sensitive prostate cancer can extend survival.

For now, men with metastatic hormone-sensitive prostate cancer should be educated about their prognosis based on their disease risk and pattern of spread, Armstrong said.

Disclosures: Astellas Pharma and Pfizer funded the study. Andrew Armstrong, MD, is a consultant with Astellas, Pfizer, Bayer, and Janssen.


1. Armstrong AJ, Shore ND, Szmulewitz RZ, et al. Efficacy of enzalutamide plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer by pattern of metastatic spread: ARCHES post hoc analyses. J Urol. Published online December 28, 2020. doi:10.1097/JU.0000000000001568