The basis for the design of the first PARP inhibitors was the observation that nicotinamide(Drug information on nicotinamide) was a weak inhibitor of PARP activity. Like nicotinamide, agents currently available are designed to inhibit PARP catalytic activity, rather than DNA binding or homodimerization. Several PARP inhibitors are presently being evaluated in both solid and hematologic malignancies (see Tables 1 and 2). Studies have been performed in populations of women with BRCA-associated malignancy, as well as in less highly selected groups of patients.
Studies in BRCA-Associated Cancer
• Olaparib (AZD2281, KU0059436)—The only published studies directly examining the potential for PARP inhibition to impact BRCA-associated cancer through synthetic lethality have been conducted with olaparib. Olaparib is a substituted 4-benzyl-2H-phthalazin-1-one that possesses high inhibitory enzyme and cellular potency for both PARP1 and PARP2. Fong et al recently published the results of an expanded single-agent phase I study in which an effort was made to oversample patients with BRCA-associated malignancy. After reaching a maximum tolerated dose (MTD) in the traditional phase I portion, the investigators expanded the study to include a number of additional patients with documented BRCA-associated cancer.
A total of 60 patients enrolled, 22 of whom had mutations in BRCA1 or BRCA2. Another woman with ovarian cancer had a strongly suggestive family history but declined testing. The patients had breast cancer (15%), ovarian cancer (35%), colorectal cancer (13%), melanoma (7%), sarcoma (7%), or prostate cancer (5%). The MTD was noted to be 400 mg bid, with reversible dose-limiting toxicity noted at a dose of 400 mg po bid (grade 3 mood alteration and fatigue in 1 of 8 patients) and, more prominently, at 600 mg po bid (grade 4 thrombocytopenia and grade 3 somnolence in 2 of 5 patients). The investigational agent was well tolerated overall, with mild gastrointestinal side effects being noted in a minority of patients below the MTD. Objective tumor response was noted in 9 of 60 patients, although some clinical benefit was noted in 17 of 60 (including 12 of 19 individuals with BRCA-associated breast, ovarian, or prostate cancer). Only mutation carriers appeared to experience durable antitumor activity.
In response to the significant findings of the phase I study, a follow-up multicenter proof-of-principle phase II trial of olaparib in BRCA-deficient advanced breast cancers was performed. A total of 54 BRCA-deficient women who had received at least one prior regimen for the treatment of metastatic breast cancer were enrolled. In a single-arm, two-sequential-patient-cohort design, the first 27 patients received continuous oral olaparib in 28-day cycles at 400 mg bid. In the second cohort, 27 patients received 100 mg of olaparib po bid. The primary endpoint was overall response rate. Subjects had received a median of three prior regimens and 44 of 54 had been treated with an anthracycline and taxane. Fatigue was the most common adverse event, usually grade 1 or 2. Grade 1/2 nausea was also common. In the intent-to-treat cohort, objective response rates were 41% (n = 11) and 22% (n = 6) in patients receiving 400 mg bid and 100 mg bid, respectively. The median progression-free survival in the 400 mg bid cohort was 5.7 months, compared with 3.8 months in the 100 mg bid cohort. Similar results were observed in a concurrent study of nearly identical design evaluating the effectiveness of single-agent olaparib in the treatment of BRCA-associated ovarian cancer.
The findings of the olaparib studies have provided important empiric support for the hypothesis that PARP inhibition would be an effective treatment for cancers that harbor defects in homologous recombination repair mechanisms. These observations are now being extended in phase II studies evaluating olaparib in combination with a number of other chemotherapy agents, including platinum agents, in both BRCA-associated and sporadic malignancies.
Studies in Cancers Not Associated With BRCA Mutations
• BSI-201—Olaparib and BSI-201 are the most advanced PARP inhibitors in terms of clinical development. While the reported phase II studies of olaparib have involved subjects with BRCA-associated cancers, the reported phase II study of BSI-201 has been in the somewhat broader population of women with triple-negative breast cancer.
The structure of BSI-201 has not been published. Unlike olaparib, BSI-201 must be administered intravenously. Phase I single-agent as well chemotherapy-combination studies of BSI-201 in patients with advanced solid tumors have demonstrated that BSI-201 is safe and well tolerated.[39,40] In the first-in-human phase I study of BSI-201 in subjects with advanced solid tumors, 23 subjects were treated at seven dose levels ranging from 0.5 mg/kg to 8.0 mg/kg. All doses were well tolerated without identifying an MTD. Gastrointestinal side effects were most common (39%).
A phase Ib study evaluating BSI-201 in combination with topotecan(Drug information on topotecan), gemcitabine(Drug information on gemcitabine) (Gemzar), temozolomide(Drug information on temozolomide) (Temodar), or carboplatin(Drug information on carboplatin)/paclitaxel was also performed. Primary objectives were to evaluate safety and MTD of BSI-201 in combination with chemotherapy; a secondary objective was clinical benefit. Subjects with advanced solid tumors were treated with BSI-201 doses of 1.1 thru 8.0 mg/ kg, in combination with a physician-choice–dependent chemotherapy. BSI-201 was given intravenously (on days 1 and 4 of each week) with chemotherapy given on study day 1. All combinations were well tolerated, with none of the 21 adverse events attributed to BSI-201. A complete response was seen one patient with ovarian cancer; five patients had a partial response (1 renal carcinoma, 2 breast cancers, 1 uterine cancer, and 1 sarcoma), and 19 patients had stable disease for 2 months or more.
At the 2009 American Society of Clinical Oncology meeting, promising data was presented from a randomized phase II efficacy study investigating whether inhibiting PARP1 activity by combining BSI-201 with gemcitabine/carboplatin in metastatic triple-negative breast cancer patients improves the clinical benefit rate compared with gemcitabine/carboplatin alone. A total of 120 subjects were enrolled in this study. Primary endpoints were clinical benefit rate and toxicity. Secondary endpoints included response rate, progression-free survival, and overall survival. The addition of BSI-201 to gemcitabine/carboplatin did not appear to potentiate toxicities of gemcitabine/carboplatin alone. Adverse event profiles were comparable in the two arms, as were toxicity-related dose reductions. The interim analysis of 116 subjects (of 120 planned) showed a statistically significant improvement in median progression-free survival (6.9 vs 3.3 months; HR = 0.342; P < .0001) and median overall survival (9.2 vs 5.7 months; HR = 0.348; P = .0005) in subjects receiving BSI-201 plus gemcitabine/carboplatin (n = 57), compared with gemcitabine/carboplatin alone (n = 59). BSI-201 plus gemcitabine/carboplatin (n = 42) vs gemcitabine/carboplatin alone (n = 44) improved the clinical benefit rate (62% vs 21%, P = .0002) and objective response rate (48% vs 16%, P = .002). Updated phase II analysis of 123 randomized patients was presented at the 2009 San Antonio Breast Cancer Symposium. The combination of BSI-201 with carboplatin/gemcitabine improved median overall survival (12.2 months) compared to carboplatin/gemcitabine alone (7.7 months; P = .005; HR = 0.5; 95% CI = 0.3–0.82). As with the initial analysis, adverse events did not differ between the two arms.
A multicenter phase III randomized trial is now underway to confirm these findings. Other studies are evaluating the incremental benefit of BSI-201 in a variety of additional disease settings and drug combinations.
Drugs in Early Development
• ABT-888—ABT-888 is one of a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors. Preclinical studies in melanoma, glioma, and breast cancer models demonstrated that ABT-888 potentiated the inhibitory activity of a number of chemotherapeutic agents including temozolomide, platinums, and irinotecan(Drug information on irinotecan), as well as radiation. The pharmacokinetic and pharmacodynamic properties of ABT-888 in humans were established through a novel phase 0 study that may serve as a model for accelerating development of other novel agents. This approach facilitated the rapid deployment of ABT-888 into combination studies, which are ongoing. At this time, no efficacy results are available.
• AGO14699—AG014699, the phosphate salt of AG14447, was identified through a screening process evaluating 42 candidate agents with a number of different core structures. Subsequently, AG014699 was evaluated as a chemosensitizer in combination with temozolomide in advanced solid tumors. In the first part of the study, 27 pts with solid tumors were enrolled. They received AG014699 (IV infusion with dosing escalated) and temozolomide daily (100 mg/m2 po) × 5 every 28 days. In the second part of the study, 9 patients with metastatic melanoma received a fixed dose of AG014699, and temozolomide was increased to MTD or 200 mg/m2. Doses up to 12 mg/m2 of AG014699 and 200 mg/m2 of temozolomide were given and demonstrated to be safe, well tolerated, and inhibitory of peripheral blood lymphocyte and tumor PARP activity. No dose-limiting toxicities were observed.
A follow up phase II study in 2006 evaluated AG014699 (12 mg/m2) and temozolomide (200 mg/m2) five times daily every 4 weeks in patients with advanced metastatic melanoma. Chemotherapy-naive patients (n = 40) with advanced metastatic melanoma were enrolled. More myelosuppresion was noted in the phase II study than in the phase I study, with grade 4 thrombocytopenia (12%), grade 4 neutropenia (15%), and one toxic death attributed to febrile neutropenia. At the time of presentation, there were four partial responses and four prolonged disease stabilizations, with the remaining patients too early to evaluate. A phase II study is underway to evaluate AG014699 in known carriers of a BRCA1 or BRCA2 mutation with locally advanced or metastatic breast or advanced ovarian cancer.
• MK4827—MK4827 is currently in a phase Ia study in patients with metastatic or locally advanced solid tumors and a phase Ib study in patients with BRCAmutant–associated ovarian cancer. In the phase Ia portion, MK4287 will be administered orally once daily in 21-day cycles with a standard dose escalation schema to evaluate MTD. In phase Ib, MK4827 will be administered orally at a dose/regimen based on the phase Ia data.
• INO-1001—PARP activity appears to be important in triggering cell death in response to ischemic injury. PARP inhibitors are therefore of interest in this setting. INO-1001 has mainly been evaluated in the cardiovascular setting, including in ST-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) as well in cardiovascular surgeries requiring heart lung bypass. Studies in patients with malignancy have not been reported.
Although poly(ADP)-ribosylation has long been known to be an important cellular process, PARP inhibition as a therapeutic approach to cancer has only recently entered clinical trials. There have been notable successes in patients with BRCA-associated malignancy due to the fact that the specific DNA damage repair defect resulting from loss of BRCA function results in sensitivity to synthetic lethality through PARP inhibition. It remains to be seen whether that same mechanism will obtain in other types of cancer, such as triple-negative breast cancer. However, there may be other defects, such as loss of PTEN function, that sensitize cells to synthetic lethality by PARP inhibitors. In addition, these agents may enhance the effectiveness of traditional cytotoxic agents and radiotherapy by a more conventional chemo- or radiosensitization mechanism. The results of studies currently underway will provide a better sense of the best ways to deploy this exciting new approach in the treatment of breast and other cancers.
Financial Disclosure: Dr. Robson has received research funding from KuDOS Pharmaceuticals.