Circulating tumor cell expression analysis from the phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects (BRCAAway).
Authors: Reichert Zachery R , Hussain Maha H. A. , Lovett Jennie L , Kocherginsky Masha , Paller Channing Judith , Agarwal Neeraj , Adra Nabil , Zhang Jingsong , Picus Joel , Szmulewitz Russell Zelig , Kuzel Timothy M , Tagawa Scott T. , Bazzi Latifa A , Whang Young E. , Stephenson Ryan D. , Dreicer Robert , Shevrin Daniel , Rettig Matthew , Antonarakis Emmanuel S. , Morgan Todd Matthew 
Published: February 2025

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Background:
Approximately 25% of patients (pts) with prostate cancer have deleterious germline/somatic homologous recombination repair mutations (HRRm). BRCAAway found the combination of an androgen receptor (AR) pathway inhibitor (ARPi) and poly(ADP-ribose) polymerase inhibitor (PARPi) as first-line therapy in pts with mCRPC and BRCA1/2 and/or ATM alterations to demonstrate longer progression-free survival (PFS) vs either agent alone or sequentially. Understanding AR signaling in HRRm (BRCA2 altered especially) versus intact patients and how they relate to response is unknown and may offer insights to mechanisms of resistance/sensitivity.
Methods:
Pts were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi + Ola). Internally analyzed, pooled circulating tumor cells (CTCs) were captured via bead-based EPCAM antibody with subsequent RT-PCR for gene expression profiling. Pretreatment samples from 47 pts across the three arms were compared to a historical CRPC cohort for difference and evaluated for a predictor of poor PSA response (stable PSA or progression by PCWG3).
Results:
A high probability of CTCs was found in 23 of 47 pts (48.9%, 11 Abi, 6 Ola, 6 Abi + Ola). In comparison to historical mCRPC pts, those with HRRm did not segregate from DNA repair intact pts regarding AR signaling. Also, PSA responders did not segregate from non-responders. Focusing on those with BRCA2 HRRm (20/23, 10 Abi, 5 Ola, 5 Abi+Ola), lack of PSA response was seen in 6/20 (30%). Combining the monotherapy cohorts, higher AR expression (median 22 for nonresponders and 15 for responders) correlated with lack of PSA response (unpaired t-test p=0.03), while ARV7 (median 18 vs 12) did not but may suffer from underpowering (p=0.20). Interestingly, the Abi+Ola cohort had a median AR expression closer to nonresponders (21.3), yet all 5 responded.
Conclusions:
Enriched CTC gene profiles from BRCAAway study pts prior to therapy in all arms appear similar to non HRRm mutant pts, supporting that the AR signaling pathway is consistently altered in mCRPC regardless of HRR status. For those with BRCA2 related HRRm, high AR expression associates with poor monotherapy response (Abi or Ola), but not the combination (Abi+Ola), suggesting the combination may rescue patients with AR addiction. Clinical trial information:
NCT03012321
.

BRCA2 cohort only (n=20)

PSA ResponderMedian Gene Expression (IQR
25th/75th
)

PSA NonResponder Median Gene Expression (IQR
25th/75th
)

Unpaired t-test

Monotherapy Cohort (Abi or Ola, n=15)

AR
15.0 (13.7, 21.0)
22.0 (20.3, 23.2)
P=0.03

ARV7
12.0 (3.8, 16)
18.0 (13.1, 19.7)
P=0.20

Combination Cohort (Abi+Ola, n=5)

AR
21.3 (20.3, 22.7)
None
N/A

ARV7
16.3 (1.8, 18.0)
None
N/A