Minimally invasive genomic profiling may improve treatment of advanced prostate cancer

Nearly all patients with metastatic, castration-resistant prostate cancer could feasibly undergo clinically informative genomic profiling of cell-free DNA, according to study results published in JAMA Oncology.

This genomic profiling may provide insight into response and resistance to enzalutamide (Xtandi; Astellas, Medivation), results showed.

“Prostate cancer cells are initially reliant on circulating androgens binding and activating the endogenous androgen receptor,” Kim N. Chi, MD, clinical associate professor of medicine at University of British Columbia and senior scientist at BC Cancer Agency, and colleagues wrote. “Although androgen deprivation therapy elicits a response in most patients, progression to castration-resistant prostate cancer, driven frequently by androgen receptor reactivation, is inevitable. However, in recent years, continued targeting of the androgen receptor signaling axis with abiraterone acetate [Zytiga, Janssen] and enzalutamide has changed clinical practice and improved the OS of patients with castration-resistant prostate cancer.”

The molecular response to enzalutamide among men with metastatic castration-resistant prostate cancer is undefined, and biomarkers are needed to guide therapy decisions and understand resistance patterns.

Analysis of plasma cell-free DNA (cfDNA) has recently been recognized as a minimally invasive method to explore tissue characteristics.

Kim and colleagues obtained plasma samples from 65 men with metastatic castration-resistant prostate cancer (median age, 74 years; range, 69-79) from men assigned to daily oral enzalutamide (160 mg). Temporal plasma samples were collected at baseline, after 12 weeks of treatment, and at the end of treatment.

The researchers used the samples to determine genomic characteristics from the cfDNA associated with clinical outcomes during treatment.

PSA response rate — defined as a decline of 50% or greater from baseline, confirmed 3 or more weeks later — served as the primary outcome measure. Radiographic or clinical progression — defined as worsening disease-related symptoms necessitating a change in anticancer therapy or deterioration in ECOG performance status — served as a secondary outcome measure.

The cohort has a PSA response rate to enzalutamide of 38% (n = 25), with a median clinical/radiographic PFS of 3.5 months (95% CI, 2.1-5).

The researchers isolated cfDNA from 122 of 125 plasma samples and performed successful target sequencing in 119 samples.

Robust detection of androgen receptor mutations or copy number alterations occurred in 48% of baselines samples (n = 31 of 65) and in 60% (n = 18 of 30) of progression samples.

The researchers associated worsened PFS outcomes with detection of androgen receptor amplification (HR = 2.92; 95% CI, 1.59-5.37), heavily mutated androgen receptors ( 2 mutations; HR = 3.94; 95% CI, 1.46-10.64) and RB1 loss (HR = 4.46; 95% CI, 2.28-8.74).

Androgen receptor mutations displayed clonal selection during treatment. Patients with prior abiraterone treatment exhibited increases in glucocorticoid-sensitive androgen receptor L702H and promiscuous androgen receptor T878A.

cfDNA sequencing showed mutations or copy number alterations at the time of progression in all patients tested. This included clinically targetable alterations to DNA damage repair genes and PIK3 pathway genes, as well as a high frequency (n = 4 of 14) of activating CTNNB1 mutations.

The researchers acknowledged study limitations, including the small sample size and their inability to detect androgen receptor splice variants.

“Overall, this study demonstrates that clinically informative genomic profiling from minimally invasive blood sampling is feasible in nearly all patients with metastatic castration-resistant prostate cancer,” Chi and colleagues wrote. “Beyond the molecular landscape and clinical associations reported herein in the context of enzalutamide treatment, cfDNA therefore holds remarkable promise for the practical implementation of precision medicine programs in advanced prostate cancer.” – by Cameron Kelsall

Disclosure: Chi reports honoraria and research funding from and consultant roles with Amgen, Astellas, Bayer, Eli Lilly, Janssen, Novartis and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures.