Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with...

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Approximately 25% of metastatic castration-resistant prostate cancer (mCRPC) patients harbor deleterious germline/somatic homologous recombination repair mutations (HRRm).
• Preclinical studies indicated that poly(ADP-ribose) polymerase (PARP) inhibition synergizes with androgen receptor pathway (ARP)-targeted therapy.

Purpose of the Study:

• To evaluate the efficacy of an ARP inhibitor versus a PARP inhibitor versus their combination as first-line therapy in mCRPC patients with HRRm.

Main Methods:

• A biomarker-preselected, randomized Phase 2 trial (BRCAAway) enrolled patients with BRCA1/2 and/or ATM alterations.
• Patients were randomized to abiraterone/prednisone (Abi/pred), olaparib (Ola), or the combination (Abi/pred + Ola).
• The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response, PSA response, and safety.

Main Results:

• The combination arm (Abi/pred + Ola) demonstrated a median PFS of 39 months, significantly longer than Abi/pred alone (8.6 months) or Ola alone (14 months).
• No Grade 4/5 adverse events were reported.
• Sequential treatment arms showed comparable PFS from randomization (16 months) but were shorter than the combination arm.

Conclusions:

• In mCRPC patients with BRCA1/2 or ATM HRRm, the combination of abiraterone/prednisone plus olaparib is well-tolerated.
• This combination therapy resulted in longer PFS compared to either agent alone or sequential administration.