Impact of homologous recombination repair alterations (
HRRalt
) on survival outcomes of patients (Pts) with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Hage Chehade Chadi , Graf Ryon P , Gebrael Georges , Ozay Zeynep Irem , Sayegh Nicolas , Li Gerald , Maughan Benjamin L. , Antonarakis Emmanuel S. , McKay Rana R. , Agarwal Neeraj , Swami Umang 
Published: February 2025

205

Background:
Up to 30% of pts with advanced prostate cancer have
HRRalt
[PMID: 32343890]. The presence of tumor
HRRalt
has been associated with poor prognosis in the metastatic castration-resistant setting [PMID: 38417742]. However, the impact of
HRRalt
in patients with mHSPC is unknown. Herein, we sought to interrogate the effect of
HRRalt
on the survival outcomes of pts with mHSPC.
Methods:
This IRB-approved retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). Inclusion criteria: de novo mHSPC, tissue biopsy within 90 days of diagnosis, and initiation of androgen deprivation therapy intensification (ADTi) with androgen receptor pathway inhibitor (ARPI) or taxane within 120 days of diagnosis. Survival outcomes were compared between pts with wild-type HRR (
wtHRR
) and those with
HRRalt
in 14 pre-specified genes per the olaparib FDA label. Time to castration-resistance (TTCR) was defined from the start of therapy for mHSPC to clinical, biochemical, or radiographic progression or death. Overall survival (OS) was defined from treatment initiation for mHSPC to death, or censored at the last follow-up. TTCR and OS indexed from metastatic diagnosis, were evaluated with Cox proportional hazards models adjusted for baseline prognostic factors. OS risk intervals were left truncated to date of comprehensive genomic profiling report to adjust for immortal time. Exploratory analyses were conducted to evaluate the association of individual HRR genes on survival outcomes in subgroups with sufficient events.
Results:
637 pts were eligible and included (181
HRRalt
, 28.4%), of whom 378 received an ARPI, and 259 received a taxane. The median age of the overall cohort was 68 (IQR 61 – 75). Results are summarized (Table).
Conclusions:
This is the largest real-world study to show significantly shorter TTCR in pts with mHSPC harboring
HRRalt.
No differences were observed in OS. However,
CDK12m
was enriched for less favorable TTCR and OS for both ARPI and taxane, highlighting an unmet need. These hypothesis-generating data may inform future clinical trial design and counseling of pts with mHSPC and
HRRalt
.

Adjusted hazard ratio (aHR) for TTCR and OS.

Genetic alteration
Subgroup
TTCR (aHR; 95% CI, p)
OS (aHR; 95% CI, p)

HRRalt
vs.
wtHRR

ADT + ARPI
1.5; 1.1 – 2.0
1.1; 0.80 – 1.6

HRRalt
vs.
wtHRR

ADT + Taxane
1.7; 1.2 – 2.3
1.2; 0.88 – 1.7

BRCA1/2
alt. vs.
wtBRCA

ADT + ARPI
1.7; 1.1 – 2.5
1.1; 0.67 – 1.8

BRCA1/2
alt. vs.
wtBRCA

ADT + Taxane
1.5; 0.92 – 2.3
1.1; 0.67 – 1.8

ATMm
vs.
wtATM

ADT + ARPI
0.95; 0.50 – 1.8
0.82; 0.38 – 1.8

ATMm
vs.
wtATM

ADT + Taxane
1.4; 0.65 – 2.9
1.3; 0.53 – 3.2

CDK12m
vs.
wtCDK12

ADT + ARPI
1.7; 1.1 – 2.8
1.7; 1.0 – 3.0

CDK12m
vs.
wtCDK12

ADT + Taxane
3.2; 2.0 – 5.3
1.7; 0.98 – 2.9