A central premise of current oncology research is that exhaustive documentation of the molecular changes that underlie cancer will lead to improved outcomes, either by identifying new therapeutic targets or by predicting responsiveness to available treatments. A number of remarkable successes provide support for this hypothesis (Table 1). However, the implementation of targeted therapies in niche patient subsets presents challenges, examples of which can be seen in the history of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor development for individuals who harbor BRCA1 and BRCA2 (BRCA) mutations. Individuals with BRCA1 and BRCA2 mutations have markedly elevated risks of breast and ovarian cancer; cancers of other sites, such as pancreas and prostate, are also associated, particularly with BRCA2 mutations.1,2 Despite initial (and quite rapid) development with extremely encouraging results, efforts to obtain regulatory approval for these agents as treatment for BRCA-associated cancers seems to have stalled. This turn of events has been sobering for academics in the field, as well as for BRCA mutation carriers who actively supported the development of these compounds.


Table 1. Targeted Therapeutics

Table 1. Targeted Therapeutics

Cancer Type Molecularly Defined Subgroup Drug
Breast Estrogen receptor positive by IHC or quantitative PCR Tamoxifen, aromatase inhibitors, fulvestrant
Breast HER2 amplified or overexpressed (by IHC or FISH) Trastuzumab, lapatinib
Chronic myelogenous leukemia BCR-ABL gene rearrangement Imatinib, nilotinib, dasatinib
GI stromal tumors C-KIT mutation positive Imatinib
Colon KRAS wild type Cetuximab
Lung EGFR mutation positive Erlotinib
Lung ALK mutation positive Crizotinib
Melanoma BRAF V600E positive PLX4032 (vemurafenib)
Medullary thyroid RET mutated Vandetanib

Abbreviations: EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PCR, polymerase chain reaction.

An understanding of the role of BRCA1 and BRCA2 in the repair of double-stranded DNA damage opened a window of opportunity for targeting BRCA mutation–associated cancers. In 2005, two seminal articles described marked sensitivity of BRCA1- and BRCA2-deficient cell lines to treatment with PARP inhibitors.3,4 This sensitivity arises because DNA damage that is usually repaired by the PARP-dependent base excision repair pathway can alternatively be repaired by BRCA-dependent repair pathways. However, if the BRCA-dependent pathway is not available, as in a BRCA mutation–associated cancer cell, cell death occurs as a result of synthetic lethality. Synthetic lethality refers to the mutation or inhibition of two genes or molecular pathways that leads to cell death when inhibition of either one alone would not. Clinical trials of PARP inhibitors in mutation carriers quickly followed the preclinical observations, and an early phase I trial of olaparib documented responses in a range of BRCA mutation–associated malignancies, with limited toxicity.5 Subsequent phase II trials of single-agent olaparib in BRCA mutation–associated breast and ovarian cancer demonstrated response rates of up to 40%, again with limited toxicity.6,7 Additional phase I and II studies with this and other PARP inhibitors (including veliparib and MK-4827) have been generally (albeit not uniformly) encouraging.810 Multiple studies are underway to evaluate the use of additional PARP inhibitors in studies that include BRCA1/2 mutation carriers, such as AG014699/PF-01367338 (in A Cancer Research UK Phase II Proof of Principle Trial of the Activity of the Intravenous PARP-1 Inhibitor, AG-014699, in Known Carriers of a BRCA1 or BRCA2 Mutation With Locally Advanced or Metastatic Breast or Advanced Ovarian Cancer; A Parallel Arms Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Intravenous Poly [ADP-Ribose] Polymerase [PARP] Inhibitor PF-01367338 [AG-014699] in Combination With Several Chemotherapeutic Regimens in Adult Patients With Advanced Solid Tumor; PARP Inhibition After Preoperative Chemotherapy in Patients With Triple Negative Breast Cancer or ER/PR+, HER2 Negative With Known BRCA1/2 Mutations: Hoosier Oncology Group BRE09-146), and CEP-9722 (in An Open-Label Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 When Administered as a Single Agent in Patients With Advanced or Metastatic Solid Tumors; and An Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of CEP-9722 [a PARP-1 and PARP-2 Inhibitor] as Single-Agent Therapy and as Combination Therapy With Temozolomide in Patients With Advanced Solid Tumors).

Patients and clinical investigators eagerly awaited phase III studies to obtain regulatory approval for PARP inhibitors in BRCA-related malignancy. To date, these trials have not materialized, and a pathway to approval is not clear. Understanding why phase II success has not yet led to registration studies in mutation carriers might inform decision making in other small, molecularly defined populations.

Issues in Selection of Target Population

Patients with BRCA mutations comprise a relatively small fraction of breast cancer cases, and the economic calculus of drug development likely plays a role with respect to PARP inhibitor development in this population. Attempts are underway to expand the target population beyond mutation carriers with efforts to target BRCA-ness in sporadic tumors.11 The majority of BRCA1-associated breast cancers are of the basal-like intrinsic subtype, as are the majority of triple-negative breast cancers (TNBCs, which are estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative). BRCA1 seems to be silenced in a subset of sporadic TNBCs, either by promoter hypermethylation or by other means, and there are suggestions that other TNBCs may have defects in homology-directed repair that may not be directly related to BRCA1 deficiency. These findings have generated considerable interest in developing PARP inhibitors for TNBC.12 A randomized phase II study of carboplatin with gemcitabine chemotherapy compared with the doublet with iniparib was conducted in unselected TNBC with strikingly positive results, including an overall survival benefit.13 On the basis of these promising data, a phase III study of nearly identical design quickly followed. Unfortunately, this study failed to meet its primary objective of improvement in the combined end point of progression-free and overall survival.14 This demonstrates that attempts to expand the role of PARP inhibitors beyond BRCA1/2 mutation–associated cancers are not guaranteed to be successful, no matter how compelling the preclinical rationale. Data regarding germline BRCA1/2 status are not available at this time to determine whether mutation carriers preferentially benefited from the addition of iniparib in this study. One must note, however, that iniparib was recently reported to be a poor inhibitor of PARP1 and PARP2; therefore, this trial may not be an adequate test of PARP inhibition as a therapeutic strategy in nonhereditary TNBC.

Although proportionally small, BRCA mutation carriers still constitute a significant absolute number of patients worldwide who could benefit from these agents, particularly if they came to be used in adjuvant treatment. A targeted therapeutic agent would presumably lead to widespread BRCA testing at diagnosis to identify those who would benefit, similar to current hormone receptor and human epidermal growth factor receptor 2 tumor analysis for patients with breast cancer, and thus would additionally expand the potential number of patients who are eligible for treatment. A number of agents are approved for numerically small populations. For example, imatinib is approved in the United States for a combined population of approximately 9,000 new cases per year of GI stromal tumors, chronic myelogenous leukemia, and dermatofibrosarcoma protuberans. Only 3% of non–small-cell lung cancers are ALK mutation positive, and yet crizotinib is being rapidly developed. Vandetanib has been approved for medullary thyroid cancer, another uncommon disease. Therefore, one hopes that population size will not be an insurmountable barrier to drug development; if it is, then this obstacle will plague the development of many targeted therapies.

If one accepts that individuals with BRCA1/2 mutation–associated cancers are the most logical target population for PARP inhibitors, one must still grapple with the seemingly simplistic question of how, from a regulatory standpoint, one defines the population. In the United States, the US Food and Drug Administration requires an approved companion diagnostic test that will define the population of interest before approval is granted for an agent directed toward that population. There is presently no US Food and Drug Administration– approved diagnostic test for determining germline BRCA status, although mutation results have been used for more than a decade to make major decisions about preventive surgeries. The regulatory approval of such a diagnostic is hampered by ongoing uncertainty with respect to the status of the BRCA testing patent held by Myriad Genetics (Salt Lake City, UT). To facilitate development of molecularly targeted therapies, regulatory authorities worldwide should provide clear clinical guidance with respect to the requirements for diagnostics to be used in this setting.

Issues in the Design of Studies for Molecularly Targeted Treatments

A number of challenges confront those designing studies to obtain regulatory approval for targeted therapies. Of particular concern is selection of an appropriate comparator. Because standard alternative treatments exist for patients with BRCA mutation–associated cancers, the current so-called orphan drug mechanism is likely not appropriate. In addition, there have been few treatment trials for women with BRCA-associated breast or ovarian cancers, so there are no data on the performance of standard treatments in this specific population. For the most successful targeted therapeutics, such as imatinib in chronic myelogenous leukemia and GI stromal tumors and PLX4032 (vemurafenib) in melanoma, the standard treatment comparator had limited activity. In breast and ovarian cancer, of course, there are many more active agents. The challenge is exacerbated if regulatory approval requires an overall survival advantage compared with standard treatment. Cross-over designs are likely to confound survival end points, but the lack of a cross-over may be poorly received by study participants, advocates, and some physicians. Noninferiority designs that incorporate quality of life end points may be an option, but are less attractive if they require a larger sample size. Recruitment to large phase III studies of specialized populations with numerous standard options will require international studies with enthusiastic support from patients, advocates, and investigators. Such studies are expensive and may take longer to complete than is desirable. For all of these reasons, it would be beneficial to develop alternative regulatory pathways that employ a more refined approach than basing approval on an overall survival advantage in a phase III study with a conventional cytotoxic comparator.

The Road Ahead

Pending regulatory approval, what are physicians and patients to do about targeted agents that manifested enormous promise in early development and generated hope and enthusiasm, but have run afoul of the challenges described here? PARP inhibitor development in BRCA mutation–associated breast cancer has slowed, with no clear path to approval. There is particularly limited availability of PARP inhibitor studies for mutation carriers who have estrogen receptor–positive breast cancer. Compassionate use and extended access programs are attractive to patients, but the management and funding of such programs present challenges, not the least of which is that they may undermine the ability to conduct trials for regulatory approval. However, the current lack of access, especially after the loud and promising publicity that greeted the initial PARP trials, has the potential to undermine public faith in the concept of personalized drug development for breast cancer. This is particularly true if the challenges described are not communicated and the perception takes root that the lack of development is a result of only economic considerations.

The PARP inhibitor story is in many ways a cautionary tale for personalized medicine. To proceed requires commitment and collaboration from academics, pharmaceutical companies, and the regulatory agencies. One point is clear: we cannot allow the challenges delineated here to halt development of these compounds.

© 2011 by American Society of Clinical Oncology

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Susan M. Domchek, Abbott Laboratories (C); Geoffrey J. Lindeman, sanofi-aventis (C); Judith Balmaña, AstraZeneca (U); Steven J. Isakoff, Abbott Laboratories (U), Myriad Genetics (C); Rita Schmutzler, AstraZeneca (C), sanofi-aventis (C); Niklas Loman, Abbott Laboratories (C); Michael Friedlander, AstraZeneca (C); Andrew Tutt, AstraZeneca (C), Clovis Oncology (C), Eisai (C), sanofi-aventis (C); Mark E. Robson, Abbott Laboratories (C), AstraZeneca (C), Pfizer (C), sanofi-aventis (U) Stock Ownership: None Honoraria: Gillian Mitchell, sanofi-aventis; Rita Schmutzler, AstraZeneca, sanofi-aventis; Clare Scott, sanofi-aventis; Andrew Tutt, sanofi-aventis Research Funding: Susan M. Domchek, AstraZeneca; Geoffrey J. Lindeman, AstraZeneca, sanofi-aventis; Nadine M. Tung, AstraZeneca; Judith Balmaña, AstraZeneca, sanofi-aventis; Steven J. Isakoff, Abbott Laboratories; Rita Schmutzler, AstraZeneca; M. William Audeh, AstraZeneca; Niklas Loman, AstraZeneca; Clare Scott, AstraZeneca; Michael Friedlander, AstraZeneca; Judy E. Garber, Abbott Laboratories, AstraZeneca; Andrew Tutt, AstraZeneca, sanofi-aventis; Mark E. Robson, AstraZeneca Expert Testimony: None Other Remuneration: Rita Schmutzler, AstraZeneca

Manuscript writing: All authors

Final approval of manuscript: All authors

1. D Thompson, DF Easton: Breast Cancer Linkage Consortium: Cancer incidence in BRCA1 mutation carriers J Natl Cancer Inst 94: 13581365,2002 Crossref, MedlineGoogle Scholar
2. Cancer risks in BRCA2 mutation carriers: The Breast Cancer Linkage Consortium J Natl Cancer Inst 91: 13101316,1999 The Breast Cancer Linkage Consortium Crossref, MedlineGoogle Scholar
3. H Farmer, N McCabe, CJ Lord , etal: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Nature 434: 917921,2005 Crossref, MedlineGoogle Scholar
4. HE Bryant, N Schultz, HD Thomas , etal: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase Nature 434: 913917,2005 Crossref, MedlineGoogle Scholar
5. PC Fong, DS Boss, TA Yap , etal: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers N Engl J Med 361: 123134,2009 Crossref, MedlineGoogle Scholar
6. A Tutt, M Robson, JE Garber , etal: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial Lancet 376: 235244,2010 Crossref, MedlineGoogle Scholar
7. MW Audeh, J Carmichael, RT Penson , etal: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial Lancet 376: 245251,2010 Crossref, MedlineGoogle Scholar
8. SJ Isakoff, B Overmoyer, NM Tung , etal: A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer J Clin Oncol 28: 118s,2010 suppl abstr 1019 LinkGoogle Scholar
9. SK Sandhu, RM Wenham, G Wilding , etal: First-in-human trial of a poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers J Clin Oncol 28: 233s,2010 suppl abstr 3001 LinkGoogle Scholar
10. KA Gelmon, HW Hirte, A Robidoux , etal: Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer J Clin Oncol 28: 233s,2010 suppl abstr 3002 LinkGoogle Scholar
11. N Turner, A Tutt, A Ashworth: Hallmarks of ‘BRCAness' in sporadic cancers Nat Rev Cancer 4: 814819,2004 Crossref, MedlineGoogle Scholar
12. E Alli, VB Sharma, P Sunderesakumar , etal: Defective repair of oxidative DNA damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase Cancer Res 69: 35893596,2009 Crossref, MedlineGoogle Scholar
13. J O'Shaughnessy, C Osborne, JE Pippen , etal: Iniparib plus chemotherapy in metastatic triple-negative breast cancer N Engl J Med 364: 205214,2011 Crossref, MedlineGoogle Scholar
14. J O'Shaughnessy: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer J Clin Oncol 29: 81s,2011 suppl abstr 1007 LinkGoogle Scholar


Written on behalf of the BRCA Targeted Therapies Consortium.


No companion articles


DOI: 10.1200/JCO.2011.36.8134 Journal of Clinical Oncology 29, no. 32 (November 10, 2011) 4224-4226.

Published online September 19, 2011.

PMID: 21931031

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