Study shows clinical benefits of iniparib in combination with standard chemotherapy f

[News]

A current New England Journal of Medicine study indicates that the use of the PARP inhibitor iniparib in combination with standard chemotherapy to treat metastatic triple-negative breast cancer offers a significant increase in clinical benefit, a measure of durable response or disease stabilization, as well as an increase in progression-free survival.

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As our understanding of breast cancer biology continues to advance, this disease has come to be understood as many different diseases. As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

Original categorizations based on histology lead to lobular versus ductal subtypes. Thereafter, recognition of estrogen and progesterone status, and finally HER2 status provided further subcategorizations.

Over the past decade, molecular subtypes have characterized this disease into a series of signatures characterized by luminal, basal and other groupings with distinct prognoses. Within the context of these categories, the triple negative breast cancers have emerged as an important target.

These patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations.

Among the most active drugs in these patients are the PARP inhibitors. The excellent results with PARP inhibitors and BRCA mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

At Rational Therapeutics, Inc., in Long Beach, California, they've explored the biology of PARP inhibitors in breast and other cancers. In these investigations, the lab to applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, they have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRCA positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful, but you don't have to enter a clinical trial to find that out.

http://www.rationaltherapeutics.com

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Lisa A. Carey, M.D., and Norman E. Sharpless, M.D.

January 5, 2011 (10.1056/NEJMe1012546)

With apologies to Nietzsche, who once said “that which does not kill us makes us stronger,” sometimes that which does not kill weakens us so the next blow will be lethal. In this issue of the Journal, O'Shaughnessy and colleagues1 describe a study in which poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition was added to cytotoxic chemotherapy in an effort to set breast cancers up for that “next blow” (ClinicalTrials.gov number, NCT00540358). PARP inhibitors represent an exciting new therapeutic direction in oncology: the rational targeting of tumor-cell vulnerability during DNA repair.

Cellular DNA is under constant assault; over 150 genes, in multiple pathways, sense and repair damaged DNA. Response to DNA damage is complex and interconnected but contains several potential drug targets, including PARPs. Repair of DNA double-strand breaks is particularly interesting, since such breaks are the death-provoking effectors of therapeutic radiation and some cytotoxic chemotherapy. A favored mechanism for repair of double-strand breaks is homologous recombination, a BRCA1/2-dependent, high-fidelity process in which the homologous sequence is used to precisely repair the break. A patient with an inherited BRCA1 or BRCA2 mutation has normal BRCA function, owing to the one functional allele, but in the patient's cancer that allele is generally inactivated, rendering the tumor cells deficient in homologous recombination. PARP inhibitors exploit this tumor-specific defect in repairing double-strand breaks.

The PARPs, the most abundant of which is PARP1, are a family of nuclear enzymes that polymerize poly(adenosine diphosphate–ribose) on substrate proteins to regulate processes such as DNA repair, gene transcription, and chromatin architecture.2 PARP1 is thought to play a role in the repair of single-strand breaks, which can become toxic double-strand breaks. In cells with intact homologous recombination, double-strand breaks that occur as a result of PARP inhibition can be resolved, but in tumor cells lacking homologous recombination, PARP inhibition leads to persistent double-strand breaks, inducing cell death.3 Inhibition of homologous recombination or PARPs may be well tolerated in isolation, but combined inactivation of these distinct DNA-repair pathways results in cell death — a process called “synthetic lethality.”

Initial data on PARP inhibitors came from a phase 1 trial4 of patients with breast, ovarian, or prostate cancer who had been extensively treated previously. The patients received single-agent therapy with olaparib; there was significant tumor reduction only in patients with a germline BRCA1 or BRCA2 mutation. Further evidence of the efficacy of PARP inhibitors came from a phase 2 study5 limited to patients with a germline BRCA1 or BRCA2 mutation and with advanced breast cancer, among whom 41% had a response to olaparib alone at the recommended phase 2 dose.

BRCA1/2-associated cancers are rare, representing less than 5% of breast-cancer cases, so it is important to find out whether PARP inhibitors have activity in other cancers. A likely candidate is triple-negative breast cancer; these tumors lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).6 No biologic or targeted therapy is known to have efficacy in triple-negative breast cancer, and the prognosis is poor after relapse. Most triple-negative breast cancers are of a molecular subtype called basal-like, as are the majority of BRCA1-associated breast cancers. BRCA1-associated and sporadic basal-like breast cancers share certain biologic characteristics. This notion of shared “BRCAness” is the rationale for testing PARP inhibition in sporadic triple-negative breast cancer, since even without germline BRCA1 mutations, these tumors may harbor other lesions that diminish homologous recombination.

In the randomized, phase 2 trial by O'Shaughnessy and colleagues, patients with metastatic triple-negative breast cancer received the chemotherapy doublet gemcitabine–carboplatin either alone or in combination with the PARP inhibitor iniparib. The rate of clinical benefit, a measure of durable response or disease stabilization, was 56% in the iniparib group, as compared with 34% in the chemotherapy-alone group. There was negligible additional toxicity with iniparib. These findings alone would catch one's attention, but the improvement in progression-free survival by 2 months and improvement in overall survival by nearly 5 months with iniparib make this an even more compelling story.

Both excitement and caution are appropriate in interpreting the trial by O'Shaughnessy and colleagues. Some clear drawbacks should be noted. The cohort was small, the end points were assessed by the investigators, the gemcitabine–carboplatin regimen is unconventional, and there were imbalances at baseline in prognostically important characteristics favoring the iniparib group. 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.

Even if iniparib should reproducibly demonstrate activity in triple-negative breast cancer, questions remain about the compound used in this study. In small studies, other PARP inhibitors have not shown promising results outside of BRCA-associated breast cancer.7,8 In addition, unlike with iniparib, it has been challenging to combine several of these other agents with chemotherapy. Iniparib is a much less potent inhibitor of PARP1 (with approximately 0.1% the potency) than most other agents of this class.9 The present study does not include a pharmacodynamic assessment of PARP activity in the patients receiving iniparib, and it is unclear whether the therapeutic efficacy of this agent correlates with PARP inhibition in these patients. Therefore, the low potency, reduced toxicity when combined with chemotherapy, and possible BRCA-independent activity of iniparib distinguish it from other members of the class; at least part of its antitumor efficacy may be independent of PARP inhibition.

O'Shaughnessy and colleagues are conducting a phase 3 trial of iniparib (NCT00938652). If the phase 2 results reported here are confirmed in the larger study, PARP inhibition could be a rational approach to treating triple-negative breast cancer, and the first therapy showing a survival advantage over chemotherapy alone — but important questions would remain. First, does the activity of iniparib in this trial result from PARP inhibition or an unknown mechanism? More generally, since the “BRCAness” of triple-negative breast cancers is not proved, do PARP inhibitors as a class have activity in cancers lacking BRCA1 or BRCA2 dysfunction? Can PARP inhibition augment DNA-damaging chemotherapy administered to other subtypes of breast cancer or other types of tumor? Which DNA-damaging chemotherapy best synergizes with PARP inhibitors? Adjuvant trials of PARP inhibitors for patients with early-stage breast cancer, in which these drugs will be added to chemotherapy delivered with a curative intent, are already being developed. The many roles of PARPs outside of DNA repair raise concern that PARP inhibitors may exhibit as-yet unknown “on-target” toxic effects, such as the diet-induced obesity and insulin resistance seen in PARP1-deficient mouse models.10 In addition, the risk of secondary cancer from DNA-repair inhibition needs to be considered carefully if these agents are used for longer periods in healthier patients.

Caveats notwithstanding, these are exciting results presaging improved therapy for an underserved subgroup of patients with breast cancer and, we hope, heralding a new approach of “setting cancers up for the next blow” by combining cytotoxic chemotherapy with agents directly targeting the DNA-damage response.

This article (10.1056/NEJMe1012546) was published on January 5, 2011, at NEJM.org.

Source Information

From the Departments of Medicine and Genetics, the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill.

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Sanofi-aventis and its subsidiary, BiPar Sciences, announced on January 27th that a randomized Phase III trial evaluating iniparib (BSI-201) in patients with metastatic triple-negative breast cancer (mTNBC) did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.

Importantly, the results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study. The overall safety analysis indicates that the addition of iniparib (BSI-201) did not significantly add to the toxicity profile of gemcitabine and carboplatin.

"While this trial did not meet its primary goal, we believe that the improvement in overall survival and progression-free survival in patients in the second- and third-line setting are important findings," said Dr. Debasish Roychowdhury, Senior Vice President and Head of sanofi-aventis Oncology. "We are conducting in-depth analysis to gain further insight into these Phase III results. Sanofi-aventis remains committed to improving outcomes for patients with triple-negative breast cancer where there is high unmet medical need."

Sanofi-aventis plans to discuss these data with United States and European health authorities in the near future. Full study results will be presented at an upcoming major oncology conference. Patients with questions are encouraged to consult with their treating physicians, or call 1-800-633-1610. The current clinical development program for iniparib (BSI-201) continues in breast, lung and other cancers.

The study enrolled 519 women with mTNBC from 109 sites in the United States. Patients were randomized to receive a standard chemotherapy regimen (gemcitabine and carboplatin) on days one and eight of each 21-day cycle, with or without iniparib (BSI-201) 5.6 mg/kg, which was administered on days one, four, eight and 11 of each 21-day cycle. Patients in the study had received up to two previous lines of chemotherapy in a metastatic setting. The co-primary endpoints were overall survival and progression-free survival.

Iniparib (BSI-201) is a novel investigational anti-tumor agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity in preclinical models. Iniparib (BSI-201) is in Phase III trials for patients with squamous non-small cell lung cancer, as well as in Phase II trials for patients with breast, lung and other cancers. Iniparib is the United States Adopted Name (USAN) for the investigational agent BSI-201.

Source: BiPar Sciences

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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

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Dr. Joyce O’Shaughnessy reported Phase II data, first at the ASCO meeting, then in the NEJM, describing the efficacy of iniparib combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC). Despite the enthusiasm that surrounded Dr. O’Shaughnessy’s initial observations, the confirmatory clinical trial using iniparib combined with carboplatin and gemcitabine, then compared with carboplatin and gemcitabine did not achieve statistical significance. That is, the trial was negative and the combo of iniparib with carboplatin plus gemcitabine was not proven superior.

Based on this, Dr. Robert Nagourney initiated a study of both iniparib and olaparib in human breast cancer specimens. His results were reported at the ASCO meeting. What happened? Quite a few things.

First, it turned out that iniparib, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved.

Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response.

Finally, Dr. Nagourney originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled his recommended dose in this patient population.

Dr. Nagourney, like other investigators, entered into his original studies of these molecules believing iniparib to be a PARP inhibitor. To his surprise, and in retrospect, a direct comparison of olaparib (AZD2281) to inapaprib (BSI201) revealed no correlation. He described this in his abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).” Thus, his human tumor primary culture analysis scooped the ASCO investigators.

What has been learned? First, iniparib is not a true PARP inhibitor. Second, the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for this trial). Finally, that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents.

Source: Rational Therapeutics

Take Home Message: In retrospect, a direct comparision of olaparib to inapaprib revealed no correlation. Thus, human tumor primary culture analysis scooped the investigators. Iniparib is not a true PARP inhibitor.