Iniparib Extends Overall Survival In Metastatic Triple-Negative Breast Cancer

[News]

Women with an aggressive subtype of metastatic breast cancer appear to live an average of almost five months longer when treated with iniparib plus chemotherapy, compared to chemotherapy alone, the results of a randomized Phase-II trial show...

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[gdpawel]

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

[gdpawel]

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.

[parpinhibitor]

Early on leads to cancer of the breast with a brand new class of drug, which suppresses PARP Inhibitor, or poly(adenosine-disposphate-ribose) polymerase, have produced an impressive quantity of excitement, thinking about the investigational drugs won’t achieve the marketplace for a while yet.
The most recent enthusiasm originates from the findings of phase 1 trial using the PARP-1 inhibitor olaparib (AstraZeneca), released online June 24 within the Colonial Journal of drugs, which indicate the agent has antitumor activity in breast, ovarian, and prostate cancer connected with BRCA1 and BRCA2 strains.
However, there is also considerable enthusiasm of these new agents in the recent American Society of Clinical Oncology (ASCO) meeting, where phase 2 results with olaparib were presented, and where phase 2 results with another PARP-1 inhibitor, BSI-201 (BiPar Sciences), were selected for any plenary session. One expert in the meeting referred to the PARP inhibitors as “very promising” and designated the BSI-201 trial as “probably the most exciting findings in cancer of the breast inside a very long time,” as formerly reported by Medscape Oncology.
Now an editorial within the Colonial Journal of drugs notes that phase 1 trial results, for example individuals with olaparib, usually don’t merit space in exclusive journals, however these are unusual conditions.This trial not just reviews important results ?a additionally, it points to a different direction in the introduction of anticancer drugs.
In a nutshell, the kinase inhibitors, which reflect a method of drug development referred to as “synthetic lethality,” show antitumor activity with no toxicity connected with conventional chemotherapy.
Clinical Benefit With Minimal Negative Effects
Within the just-released phase 1 study of olaparib,12 of 19 patients who have been BRCA service providers coupled with ovarian, breast, or cancer of the prostate had a degree of of clinical benefit, and 9 had reactions based on RECIST criteria. In addition, the drug had an “acceptable” adverse-effect profile, write the authors, brought by author Peter C. Fong, MD, in the Royal Marsden National Health Service Foundation Rely upon Sutton, England. Additionally they write the “negative effects which were a minimum of possibly associated with olaparib were largely of grade one or two.Inch
Inside a phase 2 study of olaparib presented at ASCO, carried out in females with BRCA1 or BRCA2 strains and advanced cancer of the breast that endured despite previous treatment, several third of patients had tumor shrinkage. In another study of olaparib presented in the meeting, 1 / 3 of 33 women with advanced chemotherapy-refractory ovarian cancer who have been given a 400 mg daily dose from the drug had response based on RECIST.
However, in the meeting, these results with olaparib were overshadowed somewhat through the news about BSI-201, that was more prominent since the findings were presented in a plenary session, an usual forum for phase 2 results.In conjunction with conventional chemotherapy, BSI-201 considerably enhanced overall and progression-free survival in females with metastatic triple-negative cancer of the breast, in comparison with chemotherapy alone, reported by Medscape Oncology.
The adverse occasions connected using the mixture of BSI-201 and chemotherapy were much like individuals connected with chemotherapy alone, stated investigator Joyce O’Shaughnessy, MD, from Baylor Charles A Sammons Cancer Center in Dallas, Texas, at ASCO. “BSI-201 doesn’t add toxicity,” stated Dr. O’Shaughnessy.
New Direction Defined: Synthetic Lethality
PARP-1 is definitely an enzyme involved with DNA repair, particularly in the repair of tumor cells, Dr. O’Shaughnessy described.
Agents that behave as inhibitors of PARP-1 effectively disarm ale cancer cells to correct themselves and make the dying of individuals cells, write the editorialists, Drs. Iglehart and Silver.Importantly, PARP inhibition, which kills cancer cells, spares identical normal cells that lack cancer-related alteration, for example individuals of mutated BRCA1 and BRCA2.Thus, a target gene must be learned that, when mutated or restricted chemically, kills cells that harbor a particular cancer-related alteration, they continue.
In cells that carry BRCA1 and BRCA2 strains, one of the 2 major DNA repair techniques, referred to as homologous recombination, is nonfunctional. However, another major repair method, referred to as base-excision repair, makes up for your loss. PARP-1 inhibition hinders that base-excision repair. Thus, the PARP-1 enzyme is really a target that, once hit and restricted, results in cell dying.Cancer patients with BRCA1 and BRCA2 strains aren’t the sole candidates for PARP-1 inhibition, the editorialists.You will find probably other growths with defects in homologous recombination which should make sure they are targets for PARP inhibition therapy.”You will find probably other growths with defects in homologous recombination which should make sure they are targets for PARP inhibition therapy,” they write.
The olaparib study was based on KuDOS Pharmaceutical drugs, that is possessed by AstraZeneca. A few of the researchers within the study will benefit financially from patents held on PARP inhibitors. Other researchers are employees from the drug companies involved.