A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.

Authors

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Atish Dipankar Choudhury

Dana-Farber Cancer Institute, Boston, MA

Atish Dipankar Choudhury , Wanling Xie , Mamta Parikh , Daniel Lee , Elizabeth R. Kessler , David Johnson Einstein , Bose Kochupurakkal , Kent William Mouw , Eliezer Mendel Van Allen , L. Austin Doyle , Alan D. D'Andrea , Mary-Ellen Taplin , Geoffrey Shapiro

Organizations

Dana-Farber Cancer Institute, Boston, MA, University of California Davis Comprehensive Cancer Center, Sacramento, CA, Natl Cancer Inst, Germantown, MD, University of Colorado Anschutz Medical Campus, Aurora, CO, Beth-Israel Deaconess Medcl Ctr, Boston, MA, Dana-Farber Cancer Institute, Brookline, MA, Greenbaum Cancer Center, Baltimore, MD

Research Funding

U.S. National Institutes of Health
U.S. National Institutes of Health.

Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191). Clinical trial information: NCT03517969

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Abstract Details

Meeting

2020 Genitourinary Cancers Symposium

Session Type

Trials in Progress Poster Session

Session Title

Trials in Progress Poster Session A: Prostate Cancer

Track

Prostate Cancer - Advanced,Prostate Cancer - Localized

Sub Track

Therapeutics

Clinical Trial Registration Number

NCT03517969

Citation

J Clin Oncol 38, 2020 (suppl 6; abstr TPS252)

Abstract #

TPS252

Poster Bd #

N18

Abstract Disclosures