TALAPRO-1 is an international phase 2 study (NCT03148795) evaluating the efficacy of talazoparib monotherapy after taxane and second generation anti-androgen therapy in mCRPC patients found to have defects in DNA damage repair. Interim analysis of this trial was presented as a poster at ASCO 2020, which revealed an overall response rate of 26.7% for talazoparib monotherapy. This poster investigated a subset of patients on this trial to determine the proportion of DDR alterations that were germline versus present only in the tumor (somatic) and explore whether this distribution correlated with response. Screening prostate biopsy samples (formalin-fixed paraffin-embedded tissue) were analyzed for alteration in DNA damage repair genes using the Foundation Medicine Inc FoundationOne assay. Germline sequencing was carried about using the Ambry Genetics CustomNext-Cancer panel.
As seen in the table below, the most common alterations were in the BRCA2 (more germline than tumor), and ATM (more tumor than germline). With the important caveat that this was a small study sample, a numerically higher overall response rate was observed for germline alterations (35% versus 6.3% for somatic alterations), and homozygous alterations had a higher overall response rate relative to heterozygous alterations (42.9% versus 0%).
Given small cohort numbers from TALAPRO-1, the authors utilized the FoundationCore database to assess germline versus somatic origin and zygosity of DDR alterations in 1781 prostate tumors. BRCA2 alterations tended to be homozygous and germline, where as ATM alterations were more often somatic and split between homo- and heterozygous.
Overall, this poster established the feasibility of applying tumor and germline mutational testing panels for DDR deficiency to samples in TALAPRO-1 and offered some insight into the distribution of DDR alterations between somatic and germline tissue. The relationship between zygosity and response to talazoparib requires larger numbers of samples, which the authors suggest will be forthcoming.
Presented by: Niven Mehra, MD, PhD, Consultant in Medical Oncology, Department of Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020
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