Prognostic significance of PSA>0.2 after 6-12 months treatment for metastatic hormone-sensitive prostate cancer (mHSPC) intensified by androgen-receptor pathway inhibitors (ARPI): A multinational real-world analysis of the IRONMAN registry.

5002 Background: Phase III post-hoc analyses show poor prognosis of PSA >0.2 in mHSPC treated by androgen deprivation therapy (ADT) and ARPI, but it remains unclear 1) when PSA cutoffs should be interpreted for prognostic significance, and 2) how PSA cutoffs may differ in real-world multinational data. IRONMAN (International Registry for Men with Advanced Prostate Cancer) prospectively enrolled mHSPC patients from 16 countries and is a unique large data set to investigate these questions. Methods: Patients with mHSPC who received ADT, ARPI +/- docetaxel with PSA data enrolled in the IRONMAN registry were included. 3 PSA strata (>0.2, 0.02 to 0.2, and <0.02ng/ml) were defined at 6- and 12-months (primary analysis) after treatment start. Multivariable Cox proportional hazard regression models were constructed for overall survival (OS) and progression-free survival (PFS, as defined by any of biochemical, radiographic or clinically progression) with adjustment for disease characteristics. A 12-month landmark population was constructed to determine conditional OS and PFS in each PSA stratum. Results: 1288 patients received ADT and ARPI within 90 days of IRONMAN enrolment and met inclusion. Key characteristics were median age 70 years, 69.5% de-novo metastatic, 59% Gleason 8-10, 73% Caucasian, 8.2% Black, 1.5% Asian, 7.3% lung metastases, 3.4% liver metastases, and 53.2% enrolment from centers outside US/Canada. Intensification agents were: abiraterone acetate (576, 44.7%), apalutamide (283, 22.0%), darolutamide (135, 10.5%), or enzalutamide (294, 22.8%), and 122 (8.7%) received docetaxel in addition to ADT-ARPI. PSA at 6, 12 month landmarks respectively were: <0.02 (10%, 21%); 0.02-0.2 (41%, 45%); >0.2 (49%, 34%), with 70% of patients with 6-month PSA >0.2 retained at 12-months. Outcome data in the 12-month landmark cohort are detailed in Table 1, with 3-year OS for the PSA >0.2 stratum significantly worse than the PSA<0.02 stratum (45.3 vs 92.7%, p<0.001), representing a 7-fold mortality risk in the Cox model adjusted hazard ratio (aHR) and 8-fold risk of progression. Conclusions: IRONMAN provides large real-world data validating the poor prognosis of mHSPC with PSA>0.2 after 6-12 months ADT-ARPI treatment and these patients could be targeted for intensification in future trials. Conversely, PSA<0.02 at 6-12 months defines the best prognosis and may be of interest for de-intensification strategies. OS and PFS outcomes by 12-month PSA strata. 12-mo PSA (ng/ml) n 3-yr OS [95%CI] 3-yr PFS [95% CI] OS Cox model mortality risk [95% CI] >0.2 264 45.3% [36.7-55.9] 36.7% [28.6-47.1] aHR 7.34 [3.66-14.71] 0.02-0.2 585 80.0% [74.5-85.9] 72.9% [66.9-79.1] aHR 2.16 [1.06-4.41] <0.02 439 92.7% [87.9-97.8] 93.0% [88.6-97.5] reference