Prostate: How do ATM and BRCA2 metastasis-castration-resistant prostate cancers respond to statin and PARP inhibitors?

PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC) where specific variants are present in the DNA damage repair (DDR) pathway, but patients with ATM and BRCA2 variants may treat PARPi differently
.

Recently, researchers from the United States published an article in Prostate in which they hypothesized that there may also be differences in response to statins in prostate cancer patients, two variants of ATM and BRCA2, which may inform treatment sequencing decisions
.

Patients from 11 U.
S.
academic centers were mCRPC patients (N = 158) with harmful ATM or BRCA2 mutations who were treated with statins, PARPi, or both
.
The researchers collected demographic, treatment, and survival data, performed a Kaplan-Meier analysis, and calculated a Cox-hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS)
from the time of first treatment with statins or PARPi.

A total of 58 patients with ATM mutations and 100 patients
with BRCA2 mutations were included in the study.
Forty-four (76%) patients with ATM mutations received statins or statins followed by PARPi, and 14 (24%) received PARPi or PARPi followed by statins
.
Patients with ATM mutations had a longer PFS with statin first than with PARPi first (HR: 0.
74 [95% confidence interval [CI]: 0.
37 to 1.
50]; p=0.
40）
。 Similarly, in patients with ATM mutations, those who received statins first had longer OS (HR: 0.
56 [CI: 0.
20-1.
54]; p=0.
26）
。 Among patients with BRCA2 mutations, 51 (51%) received statin therapy first and 49 (49%) received PARPi first
.
In contrast, patients with BRCA2 mutations received PARPi first had a longer PFS than those who received taxane first (HR: 0.
85 [CI: 0.
54-1.
35]; P=0.
49）
。 Similarly, patients with BRCA2 mutations who received PARPi first had longer OS (HR: 0.
75 [CI: 0.
41-1.
37]; p=0.
35）
。

PFS at the time of first statin therapy or RARPi therapy

In summary, there were differences
in response to PARPi and to statin chemotherapy in prostate cancer patients with ATM and BRCA2 mutations.
Thus, ATM and BRCA2 mutation status may help guide the choice of initial therapy when considering the sequence of PARPi versus taxane chemotherapy for patients with mCRPC with DDR mutations.

Original source:

Christopher T Su， Emily Nizialek， Jacob E Berchuck et al.
Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.
Prostate.
Nov 2022