PSA and alkaline phosphatase changes in the EORTC-1333 PEACE-3 study evaluating the addition of six cycles of radium 223 in metastatic castration-resistant prostate cancer (mCRPC) starting enzalutamide.

5062 Background: The EORTC/UNICANCER/CTI/CUOG/LACOG Peace 3 showed that adding Ra233 to enzalutamide significantly improves investigator-assessed progression-free survival (PFS) and overall survival (OS) in mCRPC with bone metastases. We examined the effect of the combination on the decline in prostate-specific antigen (PSA) and alkaline phosphatase (ALP). Methods: From 11/2015 to 03/2023, 446 men with mCRPC and bone metastasis were randomized 1:1 to enzalutamide alone (ENZ) or combined with 6 cycles of Ra223 (ENZ-RAD). The PSA/ALP response rate is estimated at 6/12 months based on the drop from baseline in all PSA/ALP evaluable patients. For PSA, any decline ≥ 50 or 90% from baseline is considered a PSA response. For ALP, any decline of ≥30% from baseline is regarded as a response. Each response needed to be confirmed by a second evaluation at least three weeks later. Time to response is from treatment start until the first date a response was observed. ALP normalization is a decline to ≤ 115 U/L in patients with baseline ALP >115 U/L. Results: PSA: The baseline median (Q1-Q3) for ENZ-RAD was 24.0 (7.8-68.8) ng/dl, and 21.4 (8.0-57.6) ng/ml for ENZ. The median time (95%CI) to a PSA response > 50% in months (mo.) was 2.79 (2.56-3.02) in the ENZ-RAD arm and 2.76 (2.63-2.79) in the ENZ arm (HR (95%CI) 1.00 (0.80-1.24)). PSA response rates ≥50% at 6 and 12 months were 77.1% (145/188) and 76.8% (109/142) in the ENZ-RAD arm, compared to 69.9% (127/182) and 66.2% (88/133) in the ENZ arm. The median time (95%CI) to a PSA response ≥ 90% in mo. was 1.87 (1.44-2.53) in the ENZ-RAD arm and 7.44 (3.67-NE) in the ENZ arm (HR (95%CI 1.48 (1.13-1.93)). PSA response rates ≥90% at 6 and 12 mo. were 50.5% (95/188) and 54.9% (78/142) in the ENZ-RAD arm, compared to 34.1% (62/182) and 37.6% (50/133) in the ENZ arm. ALP: The baseline median (Q1-Q3) ALP in the ENZ-RAD arm was 106 (78-183) UI/L, and in the ENZ arm, 124.5 (85-216). In the ENZ/RAD and ENZ arms, 45.6% (99/217) and 54.4% (122/224) of patients had ALP ≥ 115 UI/L at baseline. The ENZ-RAD arm had a median time (95%CI) to ALP response > 30% of 2.40 (1.97-2.79) mo., while the ENZ arm had a median of 3.71 (2.83-5.49) mo. (HR (95%CI) 1.42 (1.13-1.80)). ALP >30% response rates at 6 and 12 mo. were 56.5% (108/191) and 50.0% (71/142) in ENZ-RAD and 50.8% (93/183) and 47.4% (63/133) in ENZ. The median (95%CI) time to ALP normalization in the ENZ-RAD arm is 1.97 (1.87-2.50) mo. and 4.47 (2.99-14.06) mo. In the ENZ arm(HR 1.42 (1.13-1.80)). At 6 and 12 mo., the ENZ-RAD arm ALP normalization rates were 76.2 (64/84) and 77.4 (41/53), while 50.5% (47/93) and 61.3% (38/62) in the ENZ arm. Conclusions: The addition of six cycles of RA 223 to enzalutamide in the PEACE-3 trial improves PSA response time and rates (≥90%), ALP reduction time (≥30%), and ALP normalization time and rates at 6 and 12 months. Clinical trial information: NCT02194842 .