PARP INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER-POSITIVE RESULTS PUBLISHED

January 5, 2011 — The investigational agent iniparib (Sanofi-Aventis) improved a number of clinical measures, including overall survival, in women with metastatic triple-negative breast cancer, according to final phase 2 study results.

The results for iniparib, which inhibits PARP, or poly(adenosine-disposphate-ribose) polymerase, were presented earlier at the 2010 European Society for Medical Oncology Congress and have been published online January 5 in the New England Journal of Medicine.

Women who received iniparib plus gemcitabine (Gemzar; Eli Lilly) and carboplatin had better rates of clinical benefit (by 22%) and progression-free survival (by 2 months) than those treated with chemotherapy alone. Clinical benefit is a measure of disease stabilization or durable response. Notably, those treated with iniparib survived nearly 5 months longer on average.

However, overall survival was neither a primary nor secondary end point in the 123-patient randomized trial, note the authors, led by Joyce O'Shaughnessy, MD, from Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.

The small sample size "limits our assessment of overall survival," write the study authors.

They also point out that there was an imbalance between the 2 treatment groups. Patients in the iniparib group had some favorable prognostic factors, compared with the chemotherapy-alone group, such as fewer patients with 3 or more metastatic sites (57% vs 69%).

These imbalances in prognostic factors are a reason for caution when interpreting the trial results, say Lisa Carey, MD, and Norman Sharpless, MD, in an editorial that accompanies the study. They are both from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

Other reasons for caution, say the editorialists, include the small cohort and the facts that end points were assessed by investigators and that the chemotherapy combination is "unconventional."

Excitement Is Appropriate

Despite their notes of caution, Dr. Carey and Dr. Sharpless note that "excitement" about the study data is also "appropriate."

Currently, there is no standard of care for women with metastatic triple-negative disease; they are an "underserved" group of patients, say the editorialists.

A phase 3 trial of iniparib is now underway. If these phase 2 results are confirmed, then the agent would be the first to show a survival advantage over chemotherapy alone in metastatic triple-negative breast cancer, the editorialists explain.

Excitement has surrounded iniparib since early phase 2 data on the compound, then known as BSI-201, was first presented at the American Society of Clinical Oncology 2009 annual meeting. At the time, a leading breast cancer expert called the results "one of the most exciting findings in breast cancer in a long time." Overall, the development of PARP inhibitors has been a cause for enthusiasm among researchers. In another editorial, published in 2009, a pair of cancer experts called PARP inhibition a "new direction in the development of anticancer drugs."

Different Than Other PARP Inhibitors?

Although there are a number of PARP inhibitors under development, there is a suggestion that iniparib is different from the others.

In their editorial, Dr. Carey and Dr. Sharpless ask how exactly iniparib improves outcome in patients with triple-negative breast cancer. "Does the activity of iniparib in this trial result from PARP inhibition or an unknown mechanism?" they write.

The editorialists point out that in small studies, other PARP inhibitors have not shown "promising results" outside of hereditary BRCA-associated breast cancer.

As a consequence, Dr. Carey and Dr. Sharpless raise the possibility that iniparib might only benefit a subgroup of triple-negative patients — those who also carry BRCA mutations.

"We cannot tell whether the benefit from the PARP inhibitor accrued to all triple-negative tumors equally or whether the benefit preferentially accrued to a subgroup of BRCA-deficient tumors, with less effect in those without the deficiency," they write.

However, in an interview with Medscape Medical News, Dr. Carey said that it is "unlikely" that the efficacy of iniparib in triple-negative disease is limited to women with who also have BRCA1 or 2 mutations because such cancers are rare.

So why does iniparib seem to work in women with triple-negative breast cancer when other PARP inhibitors do not?

The editorialists point out that iniparib is different from other PARP inhibitors in a number of ways.

Iniparib is a "much less potent inhibitor of PARP1," which is the most common form of PARP, than "most other agents of this class." In a perhaps related matter, it has been "challenging" to combine other PARP inhibitors with chemotherapy because of toxicity. In contrast, in the current study, there was no significant difference between the 2 treatment groups in the rate of adverse events.

The editorialists also note that, in the phase 2 study, there was no pharmacodynamic assessment of PARP activity in the patients receiving iniparib. "It is unclear whether the therapeutic efficacy of this agent correlates with PARP inhibition in these patients," they write. They also say that "at least part of its antitumor efficacy may be independent of PARP inhibition."

Study Results

The phase 2 study was sponsored by BiPar Sciences, which is now a wholly owned subsidiary of Sanofi-Aventis, and was conducted at 20 centers belonging to US Oncology.

In the study, 123 women with metastatic triple-negative breast cancer underwent randomization (1:1) and received either gemcitabine and carboplatin alone or gemcitabine and carboplatin plus iniparib. Gemcitabine (1000 mg/m2 of body surface area) and carboplatin (at a dose equivalent to an area under the curve of 2) were given on days 1 and 8, and intravenous iniparib (5.6 mg/kg) was given on days 1, 4, 8, and 11 — every 21 days. Patients in the chemotherapy-alone group were allowed to cross over to the iniparib group if disease progression occurred; in the end, 51% of patients did so.

The primary end points were safety, tolerability, and the rate of clinical benefit, defined as objective response rate (complete or partial response) plus the rate of stable disease for 6 months or more. Secondary objectives included progression-free survival and objective response rate.

The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P = .01) and the rate of overall response from 32% to 52% (P = .02). The addition of iniparib also improved median progression-free survival from 3.6 to 5.9 months (hazard ratio for progression, 0.59; P = .01) and overall survival from 7.7 to 12.3 months (hazard ratio for death, 0.57; P = .01).

The most frequent grade 3 or 4 adverse events in both treatment groups included neutropenia, anemia, and thrombocytopenia. The rate of serious adverse events was similar between the chemotherapy-alone and the iniparib groups (29% vs 28%). As noted above, there was also no significant difference between the 2 groups in terms of the rate of any adverse events.

The study was funded by BiPar Sciences, now owned by Sanofi-Aventis. The article was written by 1 academic and 1 industry author, with editorial assistance from the sponsor. Dr. Carey and Dr. Sharpless have disclosed no relevant financial relationships.

New Engl J Med. Published online January 5, 2011.