For this study, patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DNA damage repair gene were detected. Because TOPARP-A used a 400 mg olaparib dose and patients with breast cancer typically use a 300 mg dose, patients in TOPARB-B were randomized 1:1 to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability.
There were 98 patients (median age 67.6 years) randomized, with 92 patients treated and evaluable for the primary endpoint. All patients had progressed on ADT, 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, and 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%), meeting threshold for primary endpoint) in the 400 mg cohort and 39% (95%CI 24-54%) in the 300 mg cohort. Over a median follow-up of 17.6 months, the overall median PFS (mPFS) was 5.4 months. The remaining outcomes from the overall analysis are as follows:
Subgroup analyses per altered gene identified indicated response rates for BRCA1/2 of 83% (mPFS 8.1 months), PALB2 57% (mPFS 5.3 months), ATM 37% (mPFS 6.1 months), CDK12 25% (mPFS 2.9 months), and others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (mPFS 2.8 months). The highest PSA50% response rates were observed in the BRCA1/2 (77%) and PALB2 (67%) subgroups.
Among patients treated with the 300 mg dose, 12.2% had a dose reduction, while 26.7% discontinued the medication secondary to adverse events. Among patients treated with the 400 mg dose, 36.7% had a dose reduction, while 10.4% discontinued the medication secondary to adverse events.
Dr. Mateo concluded his presentation of TOPARP-B with several concluding remarks:
- Olaparib has antitumor activity against mCRPC with DNA damage repair gene alterations.
- Gene aberration type matters: response rates and rPFS differ between gene subgroups – BRCA1/2-loss mCRPC patients have a response rate of 80% with rPFS > 8 months.
- Dose may matter (400 mg vs 300 mg).
- Ongoing work includes monoallelic vs biallelic, somatic vs germline mutations, and sub-clonality.
- Registration trials for PARP inhibitors are ongoing in mCRPC based on TOPARP.
Presented by: Joaquin Mateo, MD, PhD, Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA