1623P - Prognostic value of circulating tumour DNA fraction in metastatic castration-resistant prostate cancer: Insights from the ProBio trial

Background

Circulating tumour DNA (ctDNA) fraction is promising for risk stratification. We assessed the prognostic value of ctDNA detection prior to the start of a new line of systemic therapy in patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in ProBio (NCT03903835), a platform trial designed to tailor treatments based on genomic biomarker signatures.

Methods

Upon enrolment, patients with mCRPC underwent plasma cell-free DNA profiling. Patients with undetectable ctDNA (i.e. ctDNA level below 0.5% of the total cell-free DNA) were not randomised, but were followed whilst receiving standard-of-care (SOC) treatment. Patients with detectable ctDNA were randomised to either SOC (control) or an investigational arm based on pre-defined biomarker signatures. Here, we compare survival outcomes (i.e. progression-free (PFS) and overall survival (OS)) between the SOC-treated patients with detectable and undetectable ctDNA using Bayesian survival models adjusted for multiple prognostic factors. Additionally, the relationship between ctDNA levels and survival outcomes was modelled using a spike at zero model.

Results

Compared to patients with detectable ctDNA (n=56), patients with undetectable ctDNA (n=81) had a lower tumour burden, more lymph node-only disease and fewer cases with visceral involvement. Additionally, metachronous metastases and less prior systemic therapy were observed more often in patients with undetectable ctDNA. After adjusting for known prognostic factors, patients with undetectable ctDNA levels demonstrated an 89% (90% Credible Intervals (CrI) 1.44, 2.52) longer PFS time (median: 22 vs 8.4 months) and a 91% (90% CrI 1.39, 2.69) longer OS time (median: 48.2 vs 22.2 months) compared to patients with detectable ctDNA. Furthermore, we observed a linear relation between increasing levels of detectable ctDNA and shorter expected PFS and OS times.

Conclusions

ctDNA detection prior to SOC therapy for mCRPC is independently associated with inferior prognosis. Patients with undetectable ctDNA exhibit a more favourable prognosis and may be candidates for de-escalation treatment strategies.

Clinical trial identification

NCT03903835, EudraCT 2018-002350-78.

Editorial acknowledgement

Legal entity responsible for the study

Karolinska Institutet.

Funding

Karolinska Institutet.

Disclosure

All authors have declared no conflicts of interest.