ASCO 2019: TOPARP-B: A Phase II Randomized Trial of the PARP Inhibitor Olaparib for mCRPC with DNA Damage Repair Alterations

Chicago, IL (UroToday.com) DNA damage repair gene aberrations are found in approximately 20-25% of mCRPC patients. These may include germline and/or somatic mutations, with BRCA2 being the most commonly altered DNA damage repair gene. PARP inhibitors are synthetically lethal with many DNA damage repair gene aberrations including BRCA2, BRCA1, PALB2, ATM, and CDK12, however, there are different magnitudes of sensitization. Joaquin Mateo, MD, PhD and his group previously reported on the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC patients (TOPARP-A).1 At the ASCO 2019 prostate cancer session, Dr. Mateo and colleagues reported on TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DNA damage repair alterations. 

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:

ASCO2019_endpoint_analysis.png


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.

ASCO2019_gene_subgroup copy.png

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.
Clinical trial information: NCT01682772 

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

References:
  1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
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