Olaparib response may depend on DDR mutation type in mCRPC
medwireNews: The degree of response to olaparib among patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) varies according to the type of DNA damage repair (DDR) alteration the tumor carries, research shows.
The findings of the phase II TOPARP-B trial, presented at the 2019 ASCO Annual Meeting in Chicago, Illinois, USA, show that response to the PARP inhibitor was greatest among people carrying BRCA1/2 or PALB2 mutations.
Joaquin Mateo, from the Institute of Cancer Research in London, UK, explained to meeting delegates that the trial was conducted to validate the findings of TOPARP-A, which demonstrated the antitumor activity of olaparib 400 mg twice daily in patients with no molecular selection.
TOPARP-B included 98 patients with mCRPC whose tumor biopsies showed a mutation in in any gene associated with DDR or PARP inhibitor sensitivity. Nearly all of them had previously received docetaxel (100%) plus abiraterone and/or enzalutamide (90%), and 38% had previously been treated with cabazitaxel.
The patients were randomly assigned to receive olaparib at the original dose of 400 mg twice daily or at the lower dose of 300 mg twice daily, which is now approved for the treatment of breast and ovarian cancer.
After a median 17.6 months of follow-up, the overall response rate was 54.3% in the 400 mg cohort and 39.1% in the 300 mg cohort.
This included RECIST responses of 24.2% and 16.2%, respectively, PSA responses (defined as a decline of at least 50% from baseline) of 37.0% and 30.2%, respectively, and CTC conversion rates (from ≥5 cells/7.5 mL of blood at baseline to <5 cells/7.5 mL) of 53.6% and 48.1%, respectively.
Median radiographic progression-free survival (rPFS) was 5.5 months in the 400 mg group and 5.6 months in the 300 mg group.
Subgroup analyses according to the altered gene present showed the highest response rate occurred among patients with a BRCA1/2 mutation, at 83.3% of 30 patients, followed by PALB2 at 57.1% of seven patients, ATM at 36.8% of 19 patients, and CDK12 at 25.0% of 20 patients. The response rate was 20% among the 20 patients with other mutations (ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, and WRN).
Median rPFS was 8.3, 5.3, 5.8, 2.9, and 2.8 months in the BRCA1/2, PALB2, ATM, CDK12, and other mutation groups, respectively.
Mateo concluded that “[g]ene aberration type matters” in response to treatment with olaparib.
He added that “[d]ose may matter,” but pointed out that the increased response rate and longer time without radiographic progression came at the cost of a higher rate of dose reductions. Specifically, 37.7% of patients in the 400 mg group needed a dose reduction, compared with 12.2% of those in the 300 mg group.
By Laura Cowen
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