Final phase II data for the investigational drug iniparib (BSI-201) demonstrates significant clinical benefit in women with metastatic triple negative breast cancer (mTNBC) when iniparib was administered in combination with chemotherapy agents gemcitabine/carboplatin. 
Triple-negative breast cancer (TNBC) is an aggressive cancer subtype associated with defects in DNA repair mechanism, including BRCA1 dysfunction. This makes this cancer a rational target for therapy based on poly (adenosine diphosphate–ribose) polymerase (PARP) inhibition.
PARP plays a major role in cell survival and repair mechanisms, including transcription and chromatin remodeling. It is the principal member of a family of enzymes possessing catalytic capacity that binds rapidly and directly to both single- and double-strand DNA-breaks.
Researchers have noted that in the absence of DNA damage PARP function is not critical for cell survival. This has made PARP a therapeutic target for use in anti-tumor strategies designed to impair tumor growth without damaging the normal – healthy - cells. Increased expression of PARP is considered to be associated with resistance to DNA damage- inducing therapeutic agents. Drugs that inhibit this PARP may therefore contribute to cancer cell death and increased sensitivity to chemotherapy.
Research has shown that cytoplasmatic PARP expression can be detected by immunohistochemistry in all subtypes of early breast cancers and is associated with an aggressive biological tumor pattern. It can predict pathological complete response (pCR) to neoadjuvant taxane-anthracycline-based chemotherapy. 
Data presented during the 2010 meeting of the American Society of Clinical Oncology (ASCO) showed that while PARP was found to be predictive of cause-specific survival, it was not predictive of overall survival .
Iniparib (BSI-201) is a novel investigational anti-tumor agent with PARP inhibitory activity in preclinical models has demonstrated significant anti-tumor effects in several types of cancer.
Patients diagnosed with breast cancer, have their tumors routinely tested for the presence of estrogen (ER) and progesterone (PR) receptors and for the over-expression of HER2. However, 15 to 20% of all breast cancers lack over-expression of all three proteins – giving rise to the term “triple negative breast cancer” or TNBC. Research has shown TNBC can be difficult to treat, leading the disease to be associated with poorer outcomes than other types of breast cancer. Women with TNBC are not candidates for hormonal therapy such as tamoxifen or the targeted therapy Herceptin, leaving chemotherapy as the standard treatment. Nevertheless, current therapeutic options remain suboptimal. Because of the lack of effective therapies, TNBC represents an aggressive and devastating disease.
The U.S. Food and Drug Administration (FDA) granted Fast Track designation to iniparib (BSI-201) for mTNBC. The regulatory submissions are planned for Q1 2011 in the United States and Q2 2011 in the European Union.
This multicenter, open-label, randomized study included 123 women with mTNBC. The primary endpoints were safety and tolerability and clinical benefit rate of iniparib (BSI-201) defined as a complete or partial response or stable disease of at least six months. Secondary endpoints included overall response rate and progression-free survival. Overall survival also was assessed, although it was not a pre-specified endpoint of the trial. Patients received gemcitabine/carboplatin alone (chemotherapy group) or in combination with iniparib (BSI-201) until disease progression or unacceptable toxicity. Patients in the chemotherapy group whose disease progressed were allowed to cross over to the iniparib plus chemotherapy group. Efficacy analyses were conducted on the intent-to-treat (ITT) population.
Although not a pre-specified endpoint, overall survival also was significantly increased in women who received iniparib. The study, "Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer," was published in the January 5, 2011, online version of the NEJM and will be published in the January 20, 2011, print edition. These findings were presented at the 35th European Society for Medical Oncology (ESMO) Congress in Milan, Italy.
“These published data show that the addition of iniparib to gemcitabine and carboplatin provided a significant improvement in clinical benefit in women with metastatic triple negative breast cancer, an aggressive form of breast cancer with no approved standard treatments that target this particular tumor subtype,” said Joyce O’Shaughnessy, M.D., lead investigator of the study and co-chair of the Breast Cancer Research Program, Baylor-Charles A. Sammons Cancer Center, Texas Oncology, US Oncology in Dallas.
According to the study results, 56% of patients in the iniparib group showed a clinical benefit – defined as a complete or partial response or stable disease of at least six months – compared with 34% (P=0.01) of patients in the chemotherapy group alone. Median progression-free survival in the iniparib group was 5.9 months compared with 3.6 months in the chemotherapy group (95% CI (0.39-0.90) HR=0.59, P=0.01). The overall response rate was 52% in the iniparib group versus 32 percent (P=0.02) in the chemotherapy group alone. Although it was not a prespecified endpoint of the trial, median overall survival among women who received iniparib was 12.3 months, compared with 7.7 months among women who received chemotherapy alone – translating to a 43% reduction in the risk of death (95% CI, (0.36-0.90) HR=0.57, P=0.01).
In the phase II iniparib study, the most common any grade adverse events in the iniparib (BSI-201) arm were neutropenia, anemia, thrombocytopenia, fatigue/asthenia, nausea and constipation. The most common grade 3/4 adverse events in the iniparib treatment arm were neutropenia, anemia, thrombocytopenia, leukopenia and fatigue/asthenia. There were two fatal adverse events (3.4%) in the chemotherapy-alone group and three (5.3%) in the iniparib (BSI-201) group, all attributed to disease progression within 30 days of receiving study treatment. A large phase III study is ongoing and results are expected in 2011.
“The positive iniparib phase II data in this difficult to treat form of breast cancer is encouraging and underscores the innovative science and approach we have taken as we continue to investigate iniparib’s potential to address this unmet medical need, “ said Atul Dhir M.D., CEO, BiPar Sciences, a whollyowned subsidiary of Sanofi-Aventis.
Iniparib is being trialed is in phase III trials for patients with mTNBC and squamous non-small cell lung cancer, as well as in clinical trials for patients with ovarian, pancreatic, uterine and brain cancers.
A broad development program with iniparib in breast cancer and multiple trials is planned to start in the next several months. A Phase III trial in mTNBC is ongoing, and multiple new trials are planned to start in the next several months. New trials include:
- A Phase II trial in HER2-/Hormone receptor positive (ER+ and/or PR+) metastatic breast cancer
- A Phase Ib/II trial in HER2- metastatic breast cancer in combination with taxane chemotherapy
- A Phase II trial in mTNBC testing the Taxotere/Cytoxan chemotherapy combination.
 O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Chou Koo I, Sherman BM, Bradley C. Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer
 O'Shaughnessy J Osborne C. Pippen JE,. Yoffe M, Patt D, Monaghan G, Rocha C, Sherman B.M, Bradley C. Final efficacy and safety results of a randomized phase II study of the parp inhibitor iniparib (BSI-201) in combination with gamcitabine/carboplatin in metastatic triple negative breast cancer" ESMO 2010; Abstract LBA11.
 Loibl S, Mueller B, Von Minckwitz G, Blohmer JU, d. Bois A, et al. PARP expression in early breast cancer and its predictive value for response to neoadjuvant chemotherapy.J Clin Oncol 28:15s, 2010 (suppl; abstr 10511)
 Goswami J, Goyal S, Wu H, Moran MS, Haffty BG, et al. Poly(ADP-ribose) polymerase-1 (PARP-1) expression in patients treated with breast-conserving surgery and radiation therapy (BCS+RT). J Clin Oncol 28:15s, 2010 (suppl; abstr 582)
For more information:
Clinical Trial: NCT00540358. A Phase 2 Trial of Standard Chemotherapy, With or Without BSI-201, in Patients With Triple Negative Metastatic Breast Cancer