NEW YORK-After some false starts, poly (ADP-ribose) polymerase (PARP) inhibitor research appears to be heading in the right direction, with better trial designs in BRCA-associated breast cancer, according to speakers here at the Chemotherapy Foundation Symposium.
"These are exciting times in breast cancer," Mark Robson, MD, Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, said in an interview. "Seven PARP inhibitors are now in development, with two potential ways to use PARP inhibitors, either as single agents or in combination with chemotherapy or radiation therapy.
"Single agents leverage defects in homologous recombination. Combinations magnify the damage effect."
PARP inhibitors now under investigation in clinical trials, he said, include olaparib, niraparib, and BMN 673, all to be tested in upcoming Phase III trials; veliparib in Phase II trials; rucaparib in Phase I/II development; and CEP-9722 and E7016 in Phase I trials.
Early PARP-inhibitor research generated excitement, and those first trials showed that the drugs could effectively treat some patients with BRCA mutations and advanced cancers. This included patients who had already undergone multiple prior treatments with standard chemotherapy drugs.
Some patients showed benefits, enough to warrant larger trials, Robson continued. Overall, PARP inhibitors were well tolerated, although some patients developed fatigue, nausea, anemia, and low platelet counts. But after early successes, expanded trials that included more patients without BRCA mutations were less successful, and received negative attention.
Interest was renewed in the PARP inhibitor olaparib with the publication of the results of the Phase III OLYMPIAD trial in patients with metastatic BRCA breast cancer. "Single-agent olaparib resulted in a good overall response rate of about 40 percent with median progression-free survival of about six months," Robson noted.
Subsequently, significant Phase I and II trials with olaparib and veliparib have shown promising results. "The BROCADE trial shows that veliparib is an active drug in combination with chemotherapy in patients with locally recurrent or metastatic BRCA-associated breast cancer," he said.
There are differences in potencies in PARP inhibitors, and it's not clear if they deliver the same clinical outcomes. Also, not all patients respond to PARP inhibitors. Mechanisms of resistance appear to be through drug efflux, mutations, and reversion or restoration of BRCA function.
Future directions of PARP-inhibitor research, include adjuvant/neoadjuvant therapy in germ-line BRCA mutations, combination with PI3K inhibitors in triple-negative breast cancer, development of biomarkers in homologous recombination deficiency, and evaluation in other disease types, such as non-small cell lung cancer.
Multiple DNA Repair Mechanisms
In another presentation, George Somlo, MD, Director and Professor of Breast Oncology in the Department of Medical Oncology and Therapeutics Research at City of Hope National Medical Center, called PARP a ubiquitous nuclear enzyme: "There are well over a dozen family members," he said. "PARP is involved in single-stranded breaks. If left unrepaired, damaged DNA may result in genomic instability and cell death. There is an extensive response network identifying and repairing damaged DNA."
With one DNA strand intact, single-strand breaks can be repaired through nucleotide-excision repair, base-excision repair, or through mismatch repair, Somlo explained. The enzyme PARP is necessary for effective base-excision repair.
"DNA strand breaks require homologous recombination, and BRCA 1 and 2 are involved in homologous recombination. Multiple repair mechanisms can be simultaneously affected. If there is homologous recombination due to BRCA mutation, or irradiation or platinum exposure, and base excision repair due to defective PARP, the result is cell death."
Sporadic tumors, such as triple-negative breast cancer or ovarian cancers, may behave like those with BRCA mutations, due to epigenetic silencing of BRCA, or due to disruption of other members of the homologous repair pathways, he said.
Anti-platinum drugs and PARP inhibitors have both shown single-agent activity in BRCA-associated breast cancer patients. Preclinical data suggest synergism between platinum agents and veliparib. Somlo related the trial he and colleagues designed to treat women with BRCA-associated stage IV breast cancer and to compare carboplatin and veliparib versus single-agent veliparib.
To establish the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD), the researchers first conducted a Phase I trial in 28 patients, establishing the MTD at 150 mg twice daily. "Continuous daily exposure led to the best results," Somlo said. DLTs were cytopenia, granulocytopenia, and thrombocytopenia.
"The response rate and clinical benefit rate with the combination of carboplatin and veliparib were encouraging," he said. The response rate was 57 percent in all enrolled patients, with a confirmed response seen in 54 percent of eligible patients.
One-third of patients had a complete response, and one-half had a partial response. Partial responses were seen regardless of BRCA status or the site of the disease, he noted.
"Two patients are still in remission on maintenance veliparib or off therapy and in remission 22 and 17 months following enrollment. While cytopenias are a concern, the median number of cycles, nine, suggests that the combination is tolerated, and the 71 percent clinical benefit rate observed justifies further studies with this combination."
Phase II Veliparib Data
The City of Hope researchers then started a Phase II, single-agent veliparib study with the option to cross over to the carboplatin-veliparib combination if patients had disease progression on single-agent therapy.
The rationale for the study, Somlo noted, was that "data on single-agent clinical activity with most PARP inhibitors is limited, especially in BRCA carriers. Olaparib in BRCA 1 and 2 breast cancer showed a response rate of 41 percent with PFS of 5.7 months. For niraparib, two of four patients responded among BRCA-carrier breast cancer patients."
In the Phase II study, patients received veliparib at 400 mg twice daily for 21-day cycles. Upon crossing over, they received carboplatin intravenously over 30 minutes at an area under the curve (AUC) of 4 and veliparib at 150 mg twice daily. Dose adjustments and delays were allowed. The ongoing study has enrolled 32 patients to date (14 BRCA1 carriers and 18 BRCA2 carriers), median age of 45.
The dominant metastatic site was the lung for BRCA1 carriers and bone with liver for BRCA2 carriers.
Somlo reported preliminary results on 24 patients (11 BRCA1 carriers and 13 BRCA2 carriers).
Patients received a median of 3.5 treatment cycles of veliparib. Including those with early cross-over, the number of treatment cycles was six. The median time to treatment failure on veliparib alone was four months, which was extended to 8.5 months for those who crossed over. "There is a hint that cross-over may be feasible," Somlo said.
The responders have remained on therapy up to 10 and a half months. One-quarter of patients needed dose changes, and 17 percent needed dose delays during the first course of therapy.
The most notable adverse event, he said, was grade 3/4 thrombocytopenia, which was seen in one-third of patients.
In conclusion, Somlo said, "Veliparib shows clinically relevant activity as a single agent when given at 400 mg twice daily in both BRCA1- and BRCA2-associated breast cancer. The benefit of crossing over to the combination needs further evaluation.
"Combination therapy with veliparib and carboplatin may be more effective in terms of time to failure, but toxicities and dose delays are more frequently seen. The role of maintenance therapy with veliparib needs further evaluation."
Future studies, he said, need to include a combination of veliparib plus carboplatin versus veliparib alone, with cross over to carboplatin plus veliparib; carboplatin, veliparib, and paclitaxel versus carboplatin plus veliparib, with veliparib maintenance on both arms; cisplatin plus veliparib versus veliparib, with cross over to cisplatin and veliparib allowed; and a platinum compound and a taxane plus another PARP-inhibitor in a Phase I or II randomized trial, with molecular profiling.
Other studies of PARP inhibitors will likely include trials in the neoadjuvant, post-neoadjuvant, adjuvant, and metastatic setting. Still others may include molecular profile-based (beyond BRCA and PTEN) for patient selection.
"Based on the current data, I'm in favor of a more intense, maintenance approach," Somlo said.
"We are about five years into the development of PARP inhibitors. The hope is that we can emulate other diseases in which Phase II trials will lead to approval of agents."
The moderator of the session that included both presentations, Harold Burstein, MD, PhD, Associate Professor of Medicine at Harvard Medical School, said afterward in an interview: "PARP is an exciting pathway for hereditary breast cancer patients. We have had some false starts along the way. Now we are selecting patients who show a clear signal. That's important.
"It's great to see clinical trials, particularly in high-priority diseases such as hereditary breast cancer. The good news is that more trials are opening up. I hope the results end up with a breakthrough."