PARP* Inhibitors in BRCA-Associated Cancers
PARP* Inhibitors in BRCA-Associated Cancers
Approved Drugs: None; investigational agents olaparib (AZD2281) and BSI-201 are in phase I and II clinical trials; other PARP inhibitors under investigation include AGO 14699 (Pfizer), ABT-888 (Enzo), and MK4827 (Merck).
Olaparib and BSI-201 are both being studied in BRCA-deficient breast and ovarian, prostate, and other cancers; BSI-201 has shown efficacy in triple-negative breast cancer.
Currently there are eight PARP inhibitors in clinical trial development worldwide. Phase I clinical trial results have shown single-agent activity in patients with BRCA1 and BRCA2 mutations, and phase II study findings suggest a benefit in combination with chemotherapy for patients with triple-negative breast cancers, with no increase in normal tissue toxicity. PARP inhibitors garnered much enthusiasm at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO) because they offer promise in the management of difficult-to-treat BRCA-deficiency-associated cancers of the breast, ovary, and prostate, as well as “triple-negative” breast cancers that are estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER-2)-negative.
PARP, or poly (ADP-ribose) polymerase, is an enzyme that repairs damaged DNA, thereby averting programmed cell death (apoptosis). PARPs function as base-excision repair enzymes, cutting out DNA mistakes and replacing them with the correct bases. BRCA1 and BRCA2 genes are tumor-suppressor genes, which code for the DNA repair enzymes that normally repair double-stranded DNA mistakes during cell division, such as those arising from exposure to chemotherapy (eg, carboplatin and other alkylating agents, topoisomerase inhibitors).
Because this is such an important quality-control step during cell division, BRCA1 and BRCA2 have PARP enzymes as backup enzymes in case they are mutated or taken out of service. In patients with BRCA1 or BRCA2 mutations, therefore, PARP enzymes are critical to prevent the cell from undergoing apoptosis. By blocking PARP enzymes, the cancer cell has no ability to repair DNA errors, and is forced to undergo apoptosis. The condition under which a cell can still be viable with a mutation in either of the repair pathways (BRCA1/BRCA2, or PARP) but dies when both pathways (or genes) are impaired is known as synthetic lethality. Use of therapy that exploits synthetic lethality, such as PARP inhibition, has become a new direction in cancer-drug development.
PARP enzymes are “upregulated” or increased because of overexpression of the PARP-1 gene in many cancers, and this overexpression is believed to confer acquired resistance to some chemotherapy agents, with patients responding to the drug(s) initially but then ceasing to respond after a few cycles of chemotherapy. Inhibition of the PARP enzyme could make it more difficult for cancer cells to repair damaged DNA, reducing the likelihood of tumor resistance to chemotherapy.
At the ASCO annual meeting, results of two clinical trials of PARP inhibitors, either as a single agent or in combination with chemotherapy, were presented. In a small phase II trial, Tutt et al. found that olaparib given as monotherapy was highly active (38% response rate) in patients with advanced chemotherapy-refractory BRCA-deficient breast cancer, with well tolerated side effects of fatigue, nausea, vomiting, anemia, at a dose of 400 mg orally twice daily. O'Shaughnessy et al. reported findings from a randomized phase II study using the PARP inhibitor BSI-201 (BiPar Sciences) in combination with gemcitabine (Gemzar) and carboplatin, in patients with triple-negative breast cancer. Patients in the BSI-201 group had double the progression-free survival time (6.9 months, compared with 3.3 months in the control group, P < .0001) and significantly longer overall survival (9.2 months vs 5.7 months, P < .0005).
At the 2009 San Antonio Breast Cancer Symposium, O'Shaughnessy presented updated results through November 2009 that showed addition of BSI-201 to gemcitabine/carboplatin significantly improved median overall survival compared with patients receiving gemcitabine/carboplatin alone (12.2 months vs 7.7 months, P = .005). There continued to be no additional toxicity from BSI-201. In a clinical trial of single-agent therapy with olaparib, Fong et al. found that the drug had antitumor effects only in BRCA mutation-positive patients with breast, ovarian, and prostate cancer. Side effects were well tolerated in these patients, who had received multiple prior treatment regimens; they included a 5%–25% incidence of lymphopenia, anemia, diarrhea, dyspepsia, nausea, stomatitis, vomiting, anorexia, fatigue, and dizziness. Other PARP inhibitors under investigation include AGO 14699 (Pfizer), ABT-888 (Enzo), and MK4827 (Merck).
These examples of precise drug targeting to a molecular flaw in cancer are very exciting, and PARP inhibitors bring new hope for patients with BRCA-associated cancers and triple-negative breast cancers in particular.
Results of a National Cancer Institute phase 0 study of the PARP inhibitor ABT-888 in patients with a variety of treatment-refractory solid tumors and lymphomas suggest that there is significant variation in baseline levels of poly (ADP-ribose) polymerase (PAR) in tumors, and the investigators recommend that future preclinical and clinical studies of PARP inhibition assess baseline tumor PAR levels in association with treatment response. Further investigation of the mechanism of action of PARP inhibitors in combination with chemotherapy clearly is warranted.
Mechanism of Action
PARP inhibitors block the rescue DNA repair pathway in patients with BRCA1 and/or BRCA2 mutations, causing cell death. Also causes cell death in triple-negative breast cancer cells (ER-, PR-, and HER2-negative).
Olaparib: Rapidly absorbed with peak plasma 1–3 hours after dosing. Terminal elimination half-life is 5–7 hours, so drug must be administered twice daily. BSI-201: Very short half-life of 4 minutes, requiring IV administration.
(determined by clinical study)
• Olaparib: Twice-daily dosing in continuous 28-day cycles; studied doses were 400 mg and 100 mg, orally.
• BSI-201: IV given twice weekly. Combined with chemotherapy such as gemcitabine (Gemzar) and carboplatin in triple-negative breast cancer. Significant PARP inhibition at 2.8 mg/kg.
One study dose began at 0.5 mg/kg IV twice weekly and escalated to 8 mg/kg. A dose of 1.4 mg/kg resulted in adequate Cmax. No maximum tolerated dose was determined.
Teach patient about study medication, dosing, potential side effects, and self-care measures.
• BSI-201 had no additional significant toxicity; toxicity was the same in the experimental arm with BSI-201 as in the control arm with gemcitabine/carboplatin alone.
• Olaparib causes mild GI toxicity, anemia, fatigue.
Adverse Reactions (to Olaparib) by Body System (as determined in clinical trials; boldface type indicates more common events)
GI: Nausea, vomiting, diarrhea, stomatitis, anorexia, dyspepsia
Hematologic: Lymphopenia, anemia
1. Drew Y, Plummer R: The emerging potential of poly(ADP-ribose) polymerase inhibitors in the treatment of breast cancer. Curr Opin Obstet Gynecol 22(1):67–71, 2010.
2. Fong PC, et al: Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2): 123–134, 2009.
3. Iglehart JD, Silver DP: Synthetic lethality—A new direction in cancer-drug development. New Engl J Med 361(2):189–191, 2009.
4. O'Connor R, Breen L: Resistance to chemotherapy drugs. In Missailidis S (ed). Anticancer Therapeutics. New York, NY, John Wiley & Sons, 2008.
5. Tutt A, et al: Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 27(suppl 18; CRA501), 2009.
6. O'Shaughnessy J, et al: 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. J Clin Oncol 27(18s abstr 3;), 2009.
7. O'Shaughnessy J, et al: Updated results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a PARP-inhibitor, in combination with gemctiatbine/carboplatin in metastatic triple negative breast cancer (abstract 3122). Presented at the 2009 San Antonio Breast Cancer Symposium, December 9–12, 2009, San Antonio, TX, 2009.
8. Yang SX, Kummar S, Steinberg SM, et al, National Cancer Institute Phase 0 Working Group: Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas. Cancer Biol Ther 8(21):2004–2009, 2009.
Financial Disclosure: The author has no signifi cant fi nancial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.