Update on PARP Inhibitors in Breast Cancer, 2010-2011

Poly(ADP-ribose) polymerase (PARP) are a group of enzymes that are essential for base excision repair.¹ There are several members of the PARP family, of which PARP1 is the most extensively studied.^1,2 PARP1 only detects single-stranded DNA breaks and initiates repair; without PARP1, a single-stranded break is converted into a double-stranded break and repaired by homologous repair.¹ PARP inhibition shows promise in BRCA1/2- deficient tumors, which lack homologous repair capability, causing synthetic lethality (decrease in repair of both single- and double-stranded DNA breaks, leading to cell death).³ Synergy has also been demonstrated when PARP inhibitors are combined with several traditional cytotoxic agents including temozolomide (Temodar), cyclophosphamide, topotecan, paclitaxel, cisplatin, gemcitabine (Gemzar), and irinotecan.^4-12 Several PARP inhibitors are in development, with iniparib (BSI- 201), veliparib (ABT-888) and olaparib (AZD2281), being the furthest along. In the past year, PARP inhibitors have shown activity as single agents and in combination with chemotherapy, and data have been published in journals and presented as abstracts in meetings.

Iniparib
O’Shaughnessy and colleagues evaluated the efficacy of the intravenous smallmolecule PARP inhibitor, iniparib, in women with triple-negative (estrogen receptor-, progesterone receptor-, and HER2-negative) metastatic breast cancer. ⁴ In this open-label phase 2 study, 123 patients were randomized to gem citabine (1000 mg/m2) and carboplatin (AUC 2) on days 1 and 8 of a 21-day cycle with or without iniparib, which was administered to patients in that group on days 1, 4, 8, and 11. Up to 2 prior chemotherapy regimens for metastatic disease were permitted. The study allowed for patients in the control arm to cross over to the iniparib group at the time of progression.

The overall response rate (ORR) was 52% in the iniparib arm versus 32% in the chemotherapy-only group (P = .002). The median progression-free survival (PFS) was 5.9 months for patients taking iniparib compared with 3.6 months for those on chemotherapy alone (P = .01). No significant differences were observed in the frequency of adverse events between the groups. For the 51% of patients in the control group who crossed over, iniparib demonstrated only minimal antitumor activity. The authors noted that the results are prone to biases and are being confirmed in a randomized phase 3 trial.

Earlier this year, sanofi-aventis announced that a phase 3 study of iniparib failed to meet its primary end points of significant improvement in overall survival (OS) and PFS but did not offer detailed findings.¹³ A prespecified analysis of patients treated with iniparib in the second- and third-line settings reportedly demonstrated improvement in OS and PFS “consistent with what was seen in the phase 2 study,” but specific data will not be offered until the upcoming annual meeting of the American Society of Clinical On cology. It will be interesting to view data on the survival advantage for these patients and for those with a BRCA1/2 mutation.

Oliparib
Two articles published in The Lancet evaluated the novel oral PARP inhibitor olaparib in patients with BRCA1/2 mutations and advanced breast cancer or recurrent ovarian cancer. ^14,15 Both studies compared a 400- mg twice-daily dose (cohort 1) with a 100-mg twice-daily dose (cohort 2). In patients with breast cancer, the ORR was 42% in cohort 1 and 25% in cohort 2. The median PFS also seemed to be lower in cohort 2 than in cohort 1 (2.8 vs 5.7 mo, respectively).

Patients progressing after platinum chemotherapy rarely had a confirmed response when treated with oliparib. This was also seen in patients with ovarian cancer who received olaparib 400 mg twice daily. Response was confirmed in 38% of platinum-sensitive patients versus 30% of platinum-resistant patients.

The most common toxicities seen with oliparib in these trials were nausea and fatigue. It is important to note that the cohorts were not randomized; hence, one has to exercise caution in interpreting the response rates.

Conclusion
Additional novel PARP inhibitors are being investigated in early-phase trials for breast and ovarian cancer and other solid tumors. In 2010, several abstracts were presented from early-stage trials that combine PARP inhibitors with cytotoxic chemotherapy agents. For example, a phase 2 study evaluated the efficacy of veliparib in combination with temozolomide in patients with metastatic breast cancer8 and reported 1 complete response, 2 partial responses, 7 patients with stable disease (all unconfirmed), and 14 patients whose disease progressed. A number of phase 1 trials were also presented. Updated data from these and other trials could help determine the future rule for PARP inhibitors in breast cancer.

References

1. Underhill C, Toulmonde M, Bonnefoi H. A review of PARP inhibitors: from bench to bedside. Ann Oncol. 2011;22:268-279.
2. Ame JC, Splenlehauer C, de Murcia G. The PARP superfamily. BioEssays. 2004;26:882-893.
3. Leung M, Rosen D, Fields S, et al. Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. Mol Med. 2011. [Epub ahead of print.]
4. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-214.
5. Blakeley JO, Ye X, Grossman SA, et al. Poly (ADPribose) polymerase-1 (PARP1) inhibitor BSI-201 in combination with temozolomide (TMZ) in malignant glioma. J Clin Oncol. 2010;28(15S):Abstract 2010.
6. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the firstor second-line treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol. 2010;28(15S):Abstract 1018.
7. Giaccone G, Rajan A, Kelly RJ, et al. A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors. J Clin Oncol. 2010;28(15S):Abstract 3027.
8. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010;28(15S):Abstract 1019.
9. Ji JJ, Kummar S, Chen AP, et al. Pharmacodynamic response in phase I combination study of ABT-888 and topotecan in adults with refractory solid tumors and lymphomas. J Clin Oncol. 2010;28(15S):Abstract 2514.
10. Kummar S, Chen AP, Ji JJ, et al. A phase I study of ABT-888 in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. J Clin Oncol. 2010;28(15S):Abstract 2605.
11. Moulder S, Mita M, Bradely C. A phase 1b study to assess the safety and tolerability of the PARP inhibitor iniparib (BSI-201) in combination with irinotecan for the treatment of patients with metastatic breast cancer (MBC). In: Proceedings from the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 8-15, 2010; San Antonio, TX. Abstract P6-15-01.
12. Tan AR, Givvon MN, Stein RA, et al. Preliminary results of a phase I trial of ABT-888, a poly(ADPribose) polymerase (PARP) inhibitor, in combination with cyclo phosphamide. J Clin Oncol. 2010;28(15S): Abstract 3000.
13. Sanofi-aventis reports top-line results from phase III study with iniparib (BSI-201) in metastatic triplenegative breast cancer [press release]. Bridgewater, NJ: sanofi-aventis; January 27, 2011. http://sanofi-aven tis.mediaroom.com/index.php?s=43&item=310. Accessed April 1, 2011.
14. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP)-ribose polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-244.
15. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP)-ribose polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245-251.