CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.
Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.
Dr. Joyce O'Shaughnessy
Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).
Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).
Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.
Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).
Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.
The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.
It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.
Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.
Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.
"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.
TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.
Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.
"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.