Biomarkers may guide personalized therapy for castration-resistant prostate cancer

Assessment of androgen receptor gene status in plasma DNA identified patients with castration-resistant prostate cancer with worse outcomes to standard therapy, according to a multi-institution correlative biomarker study.

Standard treatment for castration-resistant prostate cancer involves inhibition of androgen receptor signaling with abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi; Astellas, Medivation).

However, duration of response and OS appear modest in some patients.

“There is, therefore, an urgent need to develop biomarker strategies to a priori identify castration-resistant prostate cancer patients who will derive minimal benefit from androgen receptor targeting and offer them an alternative treatment paradigm,” Gerhardt Attard, MD, PhD, clinician scientist at The Institute of Cancer Research and consultant medical oncologist at The Royal Marsden NHS Foundation Trust in London, and colleagues wrote.

Researchers used multiplex droplet digital PCR to retrospectively analyze plasma DNA from 265 men with castration-resistant prostate cancer to qualify androgen receptor (AR) gene status before and after chemotherapy.

The primary cohort included 73 chemotherapy-naive patients and 98 patients previously treated with docetaxel who received enzalutamide or abiraterone. OS served as the primary endpoint in this cohort.

The secondary cohort — derived from the PREMIERE trial — consisted of 94 chemotherapy-naive patients treated with enzalutamide. PSA PFS served as the primary endpoint for this cohort.

Researchers observed AR gain in 10 (14%) chemotherapy-naive and 33 (34%) chemotherapy-treated patients in the primary cohort.

A significant association appeared between AR gain and worse OS in the chemotherapy-naive (HR = 3.98; 95% CI, 1.74-9.1) and chemotherapy-treated (HR = 3.81; 95% CI, 2.28-6.37) patients.

Researchers also observed a significant association between AR gain and poorer PFS in chemotherapy-naive (HR = 2.18; 95% CI, 1.08-4.39 and previously treated patients (HR = 1.95; 95% CI, 1.23-3.11).

PSA decline of at least 50% appeared less common with AR gain in chemotherapy-naive (OR = 4.7; 95% CI, 1.17-19.17) and chemotherapy-treated (OR = 5; 95% CI, 1.7-14.91) patients.

Eight patients with AR mutations — all of whom had received docetaxel — demonstrated poorer OS (HR = 3.26; 95% CI, 1.47-not reached) and a trend for a lower rate of at least a 50% PSA decline (OR = 6.3; 95% CI, 0.72–54.59).

In the secondary cohort, 11 patients with AR gain experienced shorter PSA PFS (HR = 4.33; 95% CI, 1.94–9.68), radiographic PFS (HR = 8.06; 95% CI, 3.26–19.93) and OS (HR = 11.08; 95% CI, 2.16–56.95).

Patients with AR gain appeared less likely to have a 50% or larger decline in PSA (OR = 4.93; 95% CI, 1.3–18.75).

“The aims of our study were defined after sample collection and, therefore, larger studies with a prespecified primary objective of defining the association with outcome by plasma AR status could provide further supportive evidence for the role of AR copy number as a biomarker in castration-resistant prostate cancer,” Attard and colleagues wrote. “For level-one evidence to change clinical practice, our findings require confirmation in prospective trials where plasma AR copy number defines treatment selection.” – by Kristie L. Kahl

Disclosure: Attard reports honoraria, consulting fees, or travel support from Astellas, ESSA Pharmaceuticals, Ipsen, Janssen, Medivation, Millennium Pharmaceuticals, Sanofi-Aventis and Ventana; and grant support from Arno, AstraZeneca and Janssen. Please see the full study for a list of all other researchers’ relevant financial disclosures.