Overview of PARP Inhibitors
OCTOBER 10, 2009
Poly(ADP-Ribose) Polymerase (PARP) inhibitors have been gaining increasing attention as a possible breakthrough in the treatment of triple negative breast cancer and cancers with mutations in BRCA1, BRCA2, or PTEN genes. Several studies attesting to the efficacy of PARP inhibitors in breast and ovarian cancer were presented at the 2009 ASCO Annual Meeting. Antoinette Tan, MD, assistant professor, The Cancer Institute of New Jersey, provided an “Update on the Clinical Status of PARP Inhibitors for the Treatment of Breast Cancer” in a special session at the Breast Cancer Symposium in San Francisco, California.
DNA suffers damage from a variety of causes. Environmental factors, errors in the DNA replication process, and treatment with chemotherapy or radiotherapy can all damage DNA. This damage sometimes results in mutations that lead to cell death. The body uses several mechanisms to repair damaged DNA.
The PARP-1 enzyme plays a key role in repairing DNA single strand breaks via the base excision repair (BER) pathway. The protein binds to the site of DNA damage and, when activated, generates a chain of events that serve to recruit enzymes associated with DNA repair. Inhibiting PARP production prevents these DNA repair enzymes from being recruited, resulting in an accumulation of single strand breaks.
Double strand breaks are typically repaired using homologous recombination, in which BRCA1 interacts with BRCA2 and other proteins in an effort to restore genomic integrity. In cancer cells with BRCA1 and BRCA2 mutations, this process cannot take place and DNA repairs are carried out via the BER pathway.
Inhibiting the PARP-1 enzyme leaves cancer cells with BRCA1 and BRCA2 mutations unable to repair themselves, resulting in apoptosis, an effect referred to as synthetic lethality. PARP inhibitors are selective for the BRCA1 and BRCA2 deficient cancer cells, and they leave the patient’s normal cells, with functional BRCA1 or BRCA2, unaffected.
Studies have shown BRCA1 and BRCA2 deficient cells are significantly more sensitive to PARP inhibition compared with wild-type cells. In preclinical work, BRCA2 tumors demonstrated significant tumor regression in response to a PARP inhibitor. This has led to the development and investigation of several PARP inhibitors. Veliparib was first PARP inhibitor to undergo phase 0 testing at NCI. Other PARP inhibitors currently being researched include BSI-201 and olaparib.
Results from a phase 1 trial of olaparib in 60 patients with previously treated advanced solid tumors were published this past summer in the New England Journal of Medicine. Of the 60 patients, 22 were BRCA1 or BRCA2 carriers, and 2 carriers had breast cancer. PARP inhibition >90% was demonstrated at doses of 60 mg or more of olaparib twice daily. One patient with breast cancer had complete response and the other developed stable disease lasting 7 months. The 8 patients with ovarian cancer who had BRCA mutations experienced partial response as did 1 patient with castrate-resistant prostate cancer. Toxicities were mostly grade 1-2.
Based on this promising activity, Tutt et al initiated a phase 2 trial of olaparib in BRCA-deficient metastatic breast cancer, the results of which were discussed at the ASCO Annual Meeting. One cohort received 400 mg of olaparib twice daily; the other received 100 mg twice daily. The patients were heavily pretreated, and half the patients in each group had BRCA1 mutations. Most had triple negative breast cancer.
Results were striking, with an overall response rate (ORR) of 41% in the high-dose cohort, which included 1 complete response and 10 partial responses; and an ORR of 22% in the low-dose cohort, all of which were partial responses. PFS was 5.7 months in the high-dose cohort versus 3.8 months in the low-dose cohort. The drug showed an acceptable safety profile. Not all the mutations responded to PARP inhibition, and Dr Tan said, “Secondary BRCA2 mutations may restore BRCA expression and function, causing resistance to platinum compounds and PARP inhibitors.”
This PARP inhibitor, a small molecule prodrug with a half-life of 4 minutes, is the furthest along in clinical trials. In vitro studies found BSI-201 potentiated activity of breast cancer cell lines. This led to a clinical trial of BSI-201 with or without the DNA-damaging agents gemcitabine (Gemzar) and carboplatin. The group of patients who received chemotherapy with BSI-201 had triple the ORR and clinical benefit rate compared with the group that received chemotherapy alone. PFS was 6.9 months in the combination arm compared with 3.3 months in the chemotherapy-only arm.
A phase 3 trial of BSI-201 with or without gemcitabine and carboplatin in patients with BRCA1/2 breast cancer is underway at more than 100 sites, with approximately 100 patients already randomized, Dr Tan said.
“The clinical and preclinical data show that there is activity in patients with BRCA-related cancers as well as a subset of patients with triple negative breast cancer,” said Dr Tan. “I think these compounds have potential influence on clinical practice on several levels once they are approved.”
She questioned whether the agents might have a broader use, such as treating tumors with specific DNA repair defects. “The challenge,” she said, “is to identify them.” She suggested a major research focus should be identifying biomarkers predictive of response. Another challenge is timing administration of the PARP inhibitor in relation to the cytotoxic agent—do you give it before chemotherapy or with it, and how long do you continue?
Dr Tan said long-term side effects of PARP inhibitors need further characterization before the agents are used in adjuvant or potentially preventive settings. “Clinical trial data to date certainly support future development of these compounds,” she said.