Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de junio de 2009

Presenter: Joyce O'Shaughnessy, MD
Presenter's Affiliation: US Oncology Group
Type of Session: Plenary

  • DNA strand breaks and DNA damage caused by chemotherapy and radiation therapy are repaired by many pathways.
    • Poly(ADP-ribose) polymerase (PARP) is a key enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks.
  • BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers.
  • A previous study Farmer and Ashworth published in Nature in 2005 showed that BRCA1 or BRCA2 deficiency profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis.
    • It is important to note that these must be cells that have loss of both alleles for BRCA deficiency.
  • Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype and accounts for 15% of all breast cancers.
    • 170,000 women were diagnosed with triple negative breast cancer in 2008.
    • TNBC shares the molecular and pathologic features associated with hereditary BRCA-1 related breast cancers.
    • There are limited treatment options available for these patients and median PFS is generally 4 months or less for metastatic disease from TNBC.
  • PARP-1 is found to be upregulated in the majority of TNBCs.
    • Since BRCA-deficient cells are sensitive to inhibition of PARP1, TNBCs (which are similar to BRCA-1 related BCs) represent a rational target of PARP-inhibitor based chemotherapy.
  • The purpose of this phase II clinical trial was to evaluate BSI-201, a potent small molecule PARP1 inhibitor, in combination with gemcitiabine/carboplatin (GC) in patients with metastatic TNBC.
Materials and Methods
  • The primary objective of this study was to analyze the clinical benefit rate (CBR = CR+PR+SD>6 months) for those patients receiving BSI-201. The secondary objective was to evaluate safety, progression free survival (PFS), and overall survival (OS) in these patients.
  • Inclusion criteria:
    • Patients with metastatic TNBC (ER-/PR-/Her2neu-) who had measurable disease.
    • Patients with < or equal to 2 prior cytotoxic regimens.
    • No prior treatment with Gemcitabine/Carboplatin was allowed.
    • Stable brain metastases patients were allowed.
  • Patients were randomized (1:1) to GC alone or GC + BSI-201.
    • Treatment: Gemcitabine (1000 mg/m2) and carboplatin (AUC=2) were given on days 1 and 8, and Intravenous BSI-201 (5.6 mg/kg) was given biweekly on days 1, 4, 8, and 11 every 21 days.
    • Restaging was completed every 2 cycles.
  • Patients assigned to receive chemotherapy without BSI-201 were allowed cross over and receive BSI-201 at the time of disease progression.
  • Endpoints were CBR, PFS, and OS. Efficacy was assessed by RECIST criteria.
  • The study design had 80% power to detect CBR differences from 0.45 to 0.67.
  • 123 patients were enrolled on this study between October 2007 and March 2009.
  • Patient baseline characteristics were well-balanced between the two arms. Lung and liver were the dominant metastatic sites in these patients.
  • Efficacy results:

Control group (GC alone)

GC +BSI-201 group

p -value and HR





Objective tumor response rate





3.1 months

6.9 months

p<0.0001 HR=0.0342

Med OS

5.7 months

9.2 months

p=0.0005 HR=0348

  • Gene expression profiling was performed in 50 patients and PARP1 was found to be upregulated in TNBC according to this analysis.
  • 40% of patients who were randomized to GC have crossed over.
  • The most common severe (grades 3 and 4) side effects included neutropenia (25/57 in patients treated with GC and BSI-201 and 31/59 patients treated with GC alone), thrombocytopenia and anemia. However, there were no statistically significant differences seen in hematologic or non-hematologic toxicities between the 2 arms.
  • There were also no differences seen in the chemotherapy dose reduction between the 2 arms.
Author's Conclusions
  • PARP-1 was upregulated in most evaluable TNBC patients in this study.
  • The agent, BSI-201 was well-tolerated and efficacy results of this trial demonstrate an improvement in clinical outcomes including CBR, PFS, and OS compared with GC alone.
  • The authors conclude that the results of this study are promising and this trial justifies further investigation in a planned Phase III trial, opening in late June 2009.
Clinical/Scientific Implications
  • Triple negative breast cancer is a very aggressive form of breast cancer with low survival rates and not many treatment options available. For this reason, it is necessary to explore novel agents for this disease.
    • PARP-1 inhibition seems to be a promising agent for TNBC in previous studies.
  • The results of this well-designed Phase II trial represent an important development for a disease that currently has no approved standard of treatment. BSI-201 may provide a potential new treatment option for patients suffering from this disease.
    • Superior results (which were statistically significant) were seen for the group which received the PARP-1 inhibitor compared to the control group for all of the outcomes measured, including CBR, tumor RR, PFS, and OS.
    • Additionally, added toxicities due to the PARP-1 inhibitor were not observed in this cohort.
  • The improvement in overall survival and progression-free survival together with the responses seen in this study are promising, although it is important to remember that this is a Phase II trial and the number of patients on the study was quite small.
  • Prior to implementing this treatment in the clinic for our cancer patients, this drug must be tested in the Phase III study, which is already planned according to the authors.
  • Other interesting questions which should be addressed in future studies include:
    • What is the optimal dose and frequency of PARP inhibitors that should be used?
    • What is the ideal timing of PARP inhibitor dosing to cytotoxic agent dosing?
    • How long should one continue treatment with PARP inhibitors?
    • Is there a role for the chronic use of PARP inhibitors as preventive agents in patients with BRCA mutations?
  • Further study of this agent and other PARP inhibtors will help us determine its therapeutic potential not only in triple- negative breast cancer, but possibly in other cancer types as well.

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