Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway)

Clin Cancer Res. 2024 Oct 1;30(19):4318-4328. doi: 10.1158/1078-0432.CCR-24-1402.

Abstract

Purpose: Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms.

Patients and methods: BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety.

Results: Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11).

Conclusions: In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Androstenes* / administration & dosage
  • Androstenes* / adverse effects
  • Androstenes* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Biomarkers, Tumor / genetics
  • DNA Repair
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Phthalazines* / administration & dosage
  • Phthalazines* / adverse effects
  • Phthalazines* / therapeutic use
  • Piperazines* / administration & dosage
  • Piperazines* / adverse effects
  • Piperazines* / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors* / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors* / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / mortality
  • Prostatic Neoplasms, Castration-Resistant* / pathology

Substances

  • Phthalazines
  • olaparib
  • Piperazines
  • abiraterone
  • Androstenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • BRCA2 Protein
  • BRCA1 Protein
  • BRCA2 protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • ATM protein, human
  • BRCA1 protein, human
  • Biomarkers, Tumor