Key messages:
- Alterations in DNA damage response genes (especially BRCA2) are associated with worse outcomes from non-PARPi treatments in metastatic castration-resistant prostate cancer (mCRPC), in particular AR pathway inhibitors.
- BRCA-deficient mCRPC harbours specific genomic alterations in actionable targets that could be prioritised for future clinical trials.
Genomic alterations in DNA damage response (DDR) genes are present in 20-30% of metastatic castration-resistant prostate cancer (mCRPC).1 Alterations in these genes, especially BRCA2, confer sensitivity to PARP (poly-(ADP ribose) polymerase) inhibitors (PARPi),2 leading to approval of PARPi as monotherapy and in combination with androgen receptor pathway inhibitors (ARPI). However, the relationship between non-PARPi agents and DDR status in mCRPC remains contentious. Moreover, as durable responses to PARPi remain elusive, dissecting therapeutic vulnerabilities in DDR-altered mCRPC is critical. To address these issues, we used a targeted circulating tumour DNA (ctDNA) panel assessing 152 key genes to sequence 407 pre-treatment plasma and matched leukocyte DNA samples collected from 375 men with mCRPC.3
Overall, we found that 34.5% of patients had DDR alterations in ctDNA including 17% in BRCA2. These patients had worse clinical outcomes including significantly shorter median progression-free survival (PFS) (3.7 vs 9.9 months, p <0.001) and overall survival (OS) (18.9 vs 33.9 months, p < 0.001). Patients with BRCA2 also had notably inferior outcomes with significantly lower median PFS (3.9 vs 9.4 months, p < 0.0001) and OS (16.1 vs 30.7 months, p <0.0001).
Figure 1 - Kaplan-Meier analysis of progression-free survival and overall survival for our mCRPC cohort according to a, b the presence of any pathogenic DDR alteration, c, d BRCA1/2 (BRCA) alteration status within the cohort.
On further analysis, we found that DDR- and BRCA2-alterations were linked to worse outcomes in patients treated with ARPI with no association between any specific DDR alterations and outcomes from taxane chemotherapy.
Notably, BRCA2 zygosity (monoallelic or biallelic, see Figure 2) had similar effects on outcomes, with similar median PFS & OS compared to BRCA2-intact pts (PFS for monoallelic 3.9 months vs biallelic 3.4 months vs intact 9.8 months, & OS 16.5 vs 12.5 vs 30.7 months). We also found that BRCA-deficient mCRPC was enriched for potentially actionable genomic alterations in AR, PTEN/PI3K, tumour suppressors (TP53, RB1, and MYC), FGFR1, and CDK6.
BRCA Aberrant BRCA Wild-Type
Figure 2 - Pre-treatment genomic landscape of mCRPC patients receiving an androgen-receptor pathway inhibitor (ARPI). Inner: mechanisms of autosomal events in diploid tumour genomes leading to monoallelic and biallelic loss. The relationship between clinical outcomes and zygosity of the BRCA2 gene was assessed in this cohort.
Written by: Miyah Awad,1 Heidi Fettke,1 & Arun Azad2
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H. Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-28.
- de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A. Olaparib for metastatic castration-resistant prostate cancer. New England Journal of Medicine. 2020 May 28;382(22):2091-102.
- Fettke H, Dai C, Kwan EM, Zheng T, Du P, Ng N, Bukczynska P, Docanto M, Kostos L, Foroughi S, Brown S. BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype. EBioMedicine. 2023 Sep 1;95.