Association of baseline and on-treatment ctDNA fraction with clinical outcomes in patients with mCRPC in the PSMAfore study of
177
Lu-PSMA-617.
Authors: De Bono Johann S. , Morris Michael J. , Sartor Alton Oliver , Wei Xiao X. , Fizazi Karim , Herrmann Ken , Piulats Josep M. , Mahammedi Hakim , Logothetis Christopher , George Daniel J. , Wong Connie , Barys Louise , Rajagopal Nisha , Alanee Shaheen , Chi Kim N. 
Published: February 2025

16

Background:
In PSMAfore (NCT04689828), [
177
Lu]Lu-PSMA-617 (
177
Lu-PSMA-617) prolonged rPFS versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) progressing once on an ARPI. Baseline circulating tumor DNA (ctDNA) fraction was associated with rPFS at the second interim analysis (IA) of OS (ASCO 24). Here, we assessed the association of baseline and cycle 2 day 1 (C2D1) ctDNA fraction, and early ctDNA and prostate-specific antigen (PSA) dynamics, with rPFS and OS at the third IA of OS.
Methods:
Patients were randomized 1:1 to
177
Lu-PSMA-617 (7.4 GBq Q6W; x6) or ARPI change. Endpoints included rPFS (primary) and OS (key secondary). Plasma ctDNA fraction was analyzed at baseline and at C2D1 using an in-house custom panel. Cox regression (adjusted for 3 risk classes based on clustering of 17 baseline clinical features) and random forest (adjusted for 15 baseline clinical features) modeling were used to assess the association of ctDNA fraction and PSA with clinical outcomes at the Feb-27-2024 data cutoff.
Results:
Patients with plasma samples at baseline and C2D1 were included (
177
Lu-PSMA-617, n/N = 82/234; ARPI change, n/N = 91/234). Cox regression models adjusted for clinical features in the
177
Lu-PSMA-617 arm showed that higher ctDNA fraction was associated with shorter rPFS and OS (Table). These associations were stronger for C2D1 than baseline, both when comparing individual models and within a model including both timepoints (Table). In random forest models including clinical features and C2D1 ctDNA fraction, the total area under curves were not improved by addition of baseline ctDNA fraction (rPFS, 0.87; OS, 0.86). In the overall population, fractional decreases from baseline to C2D1 in ctDNA (
p
= 0.0015) and PSA (
p
< 0.0001) were strongly associated with longer rPFS, and were weakly correlated with one another (correlation coefficient, 0.26). In the
177
Lu-PSMA-617 arm, fractional decrease in ctDNA (
p
= 0.002) was more strongly correlated with OS than was decrease in PSA (
p
= 0.12).
Conclusions:
This exploratory analysis suggested that C2D1 ctDNA fraction was more strongly associated than baseline ctDNA fraction with rPFS and OS. Early ctDNA fraction dynamics contributed additional information in the prediction of rPFS and OS beyond PSA dynamics alone. Clinical trial information:
NCT04689828
.

Cox regression models.
a

rPFS
OS

Baseline model,

HR (95% CI);

p

6.0 (1.6–23.0); 0.0095
12.0 (3.0–48.7); 0.00052

C-index ± SE
0.69 ± 0.04
0.75 ± 0.04

C2D1 model,

HR (95% CI);

p

47.7 (10.1–226.0); < 0.0001
82.7 (16.4–417.0); < 0.0001

C-index ± SE
0.72 ± 0.03
0.77 ± 0.03

Baseline + C2D1 model

Baseline,

HR (95% CI);
p

3.1 (0.7–14.0); 0.14
2.1 (0.4–12.7); 0.41

C2D1,

HR (95% CI);
p

35.9 (7.2–180.0); < 0.0001
52.5 (7.6–362.0); < 0.0001

C-index ± SE
0.72 ± 0.03
0.79 ± 0.03

a
HRs correspond to 1 unit change in ctDNA fraction.