Although recent trials have demonstrated overall survival (OS) and metastasis free survival (MFS) benefit with the use of ARPi in high-risk nmCRPC, individual treatment outcomes may vary. This retrospective multicentre analysis explores the association between genomic mutations with ARPi treatment outcomes in nmCRPC patients to identify predictive biomarkers.

In high-risk nmCRPC patients treated with apalutamide, enzalutamide or darolutamide at APCaRI affiliated cancer centres, median MFS, OS, PSA decline ≥ 50% from baseline (PSA50), and second progression free survival (PFS2) were calculated. Next generation gene sequencing (NGS) was performed on archival tumour tissue examining for genomic alterations in 500 genes, including homologous recombination repair (HRR), mismatch repair, tumour suppressor (TS), and PI3K/AKT oncogene (OG) groups. Analysis was conducted using Cox proportional hazards regression using wildtype cases as the reference group, while adjusting for PSA doubling time and presence of pelvic lymph nodes.

Of 32 nmCRPC patients, 25 (78%) were treated with apalutamide, 5 (16%) with darolutamide and 2 (6%) with enzalutamide. 10 patients (31%) had TS/OG mutations (5 PTEN, 8 TP53, 2 PIK3CA), 3 (9%) had HRR gene mutations (2 ATM, 1 BRCA2) and 1 (3%) had 2 MLH1 mutations (microsatellite instability). All 5 patients who received subsequent therapy received abiraterone. Patients with TS/OG mutations had significantly shorter MFS (16.4 mo; HR 5.2; 95% CI 1.4 – 25.7; p = 0.018), PFS2 (22.1 mo; HR 15.4; 95% CI 1.9 – 126.3; p = 0.011) and OS (24.1 mo; HR 8.3; 95% CI 1.2 – 58.8; p = 0.035). Those with HRR mutations had significantly reduced PFS2 (median not reach [NR]; HR 40.4; 95% CI 1.6 – 1034.2; p = 0.025) and OS (NR; HR 21.7; 95% CI 1.1 – 446.1; p = 0.045). 3 (9%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations.

This analysis demonstrates that nmCRPC patient with TS/OG and HRR gene mutations have poor clinical outcomes and may benefit from close follow-up. Our results underline the need for ongoing trials which examine novel targeted therapies (e.g. PARP Inhibitors, AKT inhibitors) in these molecularly defined nmCRPC subgroups.