ASCO GU 2021: An Exploratory Gene-by-Gene Analysis of Patients with mCRPC Treated with Olaparib in the PROfound Trial

( Published in 2020, the Phase 3 PROfound trial (NCT02987543) was a phase III randomized controlled trial of olaparib versus physician’s choice of enzalutamide or abiraterone in men with metastatic castration resistant prostate cancer (mCRPC) with alterations in at least one of 15 homologous recombination repair genes who had disease progression on next-generation hormonal agent.1,2 The trial met its primary endpoint of an improvement in radiographic progression-free survival with olaparib in mCRPC with alterations in BRCA1BRCA2, or ATM (Cohort A).1 Key secondary endpoints, including improved overall survival in Cohort A, were also met.2 These results led to the approval of olaparib treatment in patients with mCRPC who had progressed on prior enzalutamide or abiraterone with homologous recombination repair alterations in the USA and with alterations in BRCA1 and/or BRCA2 in the European Union. At the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Johann De Bono and colleagues presented results of gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair genes.

Patients in PROfound were randomized to olaparib (300 mg BID; n=256) or physician’s choice of enzalutamide or abiraterone (control; n=131). The following is a summary of the trial design and endpoints:


In PROfound, the most common gene alterations were BRCA2, ATM and CDK12. Of the 160 patients with a BRCA1 or BRCA2 alteration, 13 (8.1%) had a single alteration in BRCA1, 128 (80%) had a single alteration in BRCA2 and 19 (11.9%) had a co-occurring alteration. The baseline characteristics of the patients in the gene subgroups were generally well-balanced between the study arms:


Assessment of olaparib in patients in Cohort B with rare homologous recombination repair gene alterations provides evidence of activity, which warrants further assessment. However, PPP2R2A does not show benefit (HR for risk of progression or death 6.61, 95% CI 1.41-46.41) and preclinical studies do not support PARP inhibitor sensitivity. 


Dr. De Bono concluded this updated presentation of the PROfound trial with the following summary points:

  • PROfound is the first randomized trial to prospectively demonstrate radiographic progression free survival and overall survival improvement in a molecularly defined subset of patients with prostate cancer
  • Consistent with previous epidemiological data, BRCA2, ATM,and CDK12alterations were most commonly identified, whereas alterations in other genes with a direct or indirect role in homologous recombination repair were rare (occurring in <5% of patients randomized)
  • These results expand on the radiographic progression free survival and overall survival results that had previously been reported for BRCA1and/or BRCA2, ATM,and CDK12 and show a differential sensitivity to olaparib in the treatment of patients with distinct homologous recombination repair alterations
  • These findings support the importance of genomic testing to identify patients eligible to consider olaparib treatment


Presented by Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci.  Professor Johann de Bono is Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021


  1. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med2020 May 28;382(22):2091-2102.
  2. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357.