Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

Abstract

Background: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).Methods: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. Results and Limitations:The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.Conclusions: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

Differential responses to taxanes and PARP inhibitors in ATM‐ versus BRCA2‐mutated metastatic castrate‐resistant prostate cancer

“…To address this, we did account for prior abiraterone and enzalutamide use in our analysis. Despite these limitations, we were able to collate the largest retrospective ATM‐ and BRCA2‐ mutated mCRPC cohort in the literature to our knowledge that contains detailed diagnostic and treatment data with respect to sequencing of taxane and PARP inhibitor agents in these patients 19,23 …”

“…Third, retrospective sequencing studies in the metastatic population require controlling for previous treatment courses that may have affected tumor biology at the time of receipt of the treatments of interest. To address this, we did account for prior abiraterone and enzalutamide use in our analysis.Despite these limitations, we were able to collate the largest retrospective ATM-and BRCA2-mutated mCRPC cohort in the literature to our knowledge that contains detailed diagnostic and treatment data with respect to sequencing of taxane and PARP inhibitor agents in these patients 19,23. F I G U R E 3 Progression-free survival (PFS) by first taxane or PARP inhibitor therapy, in (A) patients with ATM mutations and (B) patients with BRCA2 mutations.PARP, poly(ADP-ribose) polymerase.…”

Therapeutic sensitivity to standard treatments in BRCA positive metastatic castration-resistant prostate cancer patients—a systematic review and meta-analysis

“…In the first-line setting, we synthesized the data of 97 patients from eight articles and found PSA50 response rates of 0.52 (CI: 0.25-0.79; I 2 = 57%), 0.64 (CI: 0.43-0.80; I 2 = 0%), 0.55 (CI: 0.36-0.73; I 2 = 1%) for abiraterone, enzalutamide and docetaxel, respectively (Fig. 2) [9,22,[24][25][26][29][30][31]. Second-line data were available for 57 patients from five articles and response rates tended to be generally lower compared to the first-line setting but showed similar distributions between abiraterone, enzalutamide and docetaxel therapies; 0.36 (CI: 0.17-0.61; I 2 = 3%), 0.46 (CI: 0.24-0.70; I 2 = 0%) and 0.42 (CI: 0.22-0.65; I 2 = 2%), respectively (Supplementary Fig.…”

“…Second-line data were available for 57 patients from five articles and response rates tended to be generally lower compared to the first-line setting but showed similar distributions between abiraterone, enzalutamide and docetaxel therapies; 0.36 (CI: 0.17-0.61; I 2 = 3%), 0.46 (CI: 0.24-0.70; I 2 = 0%) and 0.42 (CI: 0.22-0.65; I 2 = 2%), respectively (Supplementary Fig. 2) [21,24,[29][30][31].…”

The role of genetic testing in prostate cancer screening, diagnosis, and treatment

“…The PROfound and TRITON2 studies led to the Food and Drug Administration (FDA) approval of Olaparib and Rucaparib for the treatment of mCRPC in patients with DNA repair mutations [74,76]. Response to PARP inhibitors, however, is heterogeneous among patients with different DNA repair gene mutations [78,79]. Patients with BRCA2 mutations seemed to demonstrate superior progression-free survival in the PROfound subgroup analysis [74], most likely because of the high rate of two hits or biallelic inactivation of BRCA2 versus ATM, RAD51C or other genes, which may not be as frequently biallelically inactivated.…”