As you know, the Phase III study of the PARP inbititor iniparib did not meet its coprimary endpoints (PFS and OS). Dr. Neil Love of Research To Practice, put together a panel to review the iniparib story, particularly the translational issues that make this far more complex than simply that of a failed drug.
The first question was asked: Is iniparib a PARP inhibitor? The best current answer to this question came out a couple of months ago at AACR, when a translational poster by Ji et al from the NCI concluded that other agents under investigation — olaparib and veliparib — inhibited the recombinant repair pathways related to PARP1 and PARP2. Iniparib on the other hand resulted in DNA damage and inhibited PARP5, PARP6 and the telomere pathway, but the significance of this is largely unknown.
Then it was asked: Does iniparib have significant antitumor efficacy in patients with TNBC (or any other patients)? If the historic trastuzumab studies in breast cancer were conducted without knowledge of HER2 status, would we now view that agent as an effective drug? The answer suggested has always been “no” in the belief that because HER2-positive tumors make up only about 20 percent of breast cancer, patients who benefited would have been diluted mathematically by nonresponders with HER2-negative tumors and thus no effect would have been seen. The panel discussed research to identify mechanisms and predictors for iniparib and many other novel agents.
The thought was: How heterogeneous is TNBC and, for that matter, breast cancer in general? US Oncology clinician Dr. Joyce O'Shaughnessy made a presentation showing disappointing results with a graphic illustrating the intrinsic subtypes of the patients who entered the study.
http://www.researchtopractice.com/RT...hives/1/slides
Most thought provoking was the heterogeneity, including participants with luminal A or luminal B subtypes. During the discussion following Joyce’s paper, Lisa Carey showed another slide that revealed a spectrum of ER/PR and HER2 subsets within all intrinsic breast cancer subtypes, including the basals, which are usually considered to be closely associated with TN disease.
Imagine what it would be like to care for people with pneumonia if bacteria and viruses could not be cultured outside the human body. Drug development would be blind, and treatment would essentially amount to a shot in the dark. Does this sound a bit like where we are with breast cancer nowadays?
But this is were this got interesting: Do some patients with TNBC without BRCA mutations have tumors with “BRCAness” and increased sensitivity to DNA-damaging agents, specifically platinums?
In the panel, Dana-Farber's Eric Winer presented a patient from his practice who participated in a trial recently reported at ASCO evaluating cisplatin and carboplatin in advanced TNBC. Eric’s 48-year-old patient received seven cycles of cisplatin and experienced a complete response. In discussing the study findings, Winer noted that approximately one third of the patients experienced objective responses. Although the comparison of cisplatin and carboplatin was not definitive, cisplatin seemed to result in somewhat greater efficacy.
http://www.asco.org/ASCOv2/Meetings/...stractID=76639
Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint
http://cancerfocus.org/forum/showthread.php?t=3251