ASCO 2018: Phase II Trial of Rucaparib in Patients with Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations

Chicago, IL ( PARP-inhibitors are a class of agents that have significant clinical activity in patients with DNA-repair mutations. Specifically, they are a class of agents that group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). PARP1 is a protein that is important for repairing single-strand break in the DNA - if such damage persist unrepaired until DNA is replicated, then the replication itself can cause double strand breaks to form. Drugs that inhibit PARP1 result in multiple double strand breaks to form in this way, and in tumors with BRCA1, BRCA2, PALB2, or other DNA-repair mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. 

Previously established to be effective in the setting of metastatic prostate cancer, in patients with established DNA-repair gene mutations, the focus is now shifting to patients with hormone-sensitive prostate cancer. Focusing specifically on patients with a germline mutation in a pre-specified group of DNA-repair genes, the authors of this trial hypothesize that PARP-inhibitors should be able to result in clinical efficacy irrespective of hormone status – if effective, for men with metastatic hormone sensitive prostate cancer (mHSPC), this trial would also provide an alternative to ADT. 

Study Design: Open-label, Single-arm, Phase II trial 

  • Men with a documented germline mutation in a homologous DNA-repair gene (BRCA1, BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) 
  • The total number of patients allowed with a non-BRCA1, -BRCA2, or –ATM mutations will be capped at 10. 
  • Ineligible for standard of care androgen-deprivation therapy 
  • PSA > 2.0 ng/dl 
  • Testosterone > 100 ng/dL 
  • A mandatory tumor biopsy will be performed prior to therapy. A second, optional tumor biopsy is planned after three months of therapy. 
  • Men must have evidence of metastatic prostate cancer with no prior systemic therapy 
  • Presence of visceral disease > 3 cm in long-axis 
  • Pain due to bone metastases 
  • Inadequate organ and bone marrow function 
Treatment Protocol: 
  • Rucaparib 600 mg po twice daily
  • Patients will be followed monthly with clinic visits, including checks for safety, labs with PSA
  • Patients will be continued until progression (clinical, biochemical or radiographic) 

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  • As this is a phase II study, primary objective is safety and initial efficacy data
  • Primary outcome: ≥ 50% decrease in PSA from baseline (PSA50 response)
  • Secondary outcomes: safety and tolerability, PSA PFS, PFS, ORR 

  • Goal recruitment is for 30 patients. Enables detection of a 50-75% PSA50 response rate with 90% power (one sided type I error of 0.1)
  • The total number of patients allowed with a non-BRCA1, -BRCA2, or –ATM mutations will be capped at 10.
  • Secondary endpoints include safety, progression-free survival, and objective response
  • Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers. 

This is an exciting study of an alternative class of agents for men with known DNA-repair mutations. As ADT is not without its adverse effects, alternative therapies are sorely needed. 

Presented By:Mark Christopher Markowski 
Co-Authors: Hao Wang, Rana Sullivan, Michael Haffner, Angelo M De Marzo, Tamara L. Lotan, Emmanuel S. Antonarakis 
Institution:Johns Hopkins University, Baltimore, MD 

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA