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
- 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.
- 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.