To PARP or Not to PARP – What Is the Question? Part 2 Perspective on the First “Disappointment” With a New Drug Class

Robert E. Henry

The Last Word

In the first article on this topic, appearing in the last issue of PMO, we looked at a sequence of events surrounding an attempt to achieve quick consensus concerning the treatment of metastatic triple-negative breast cancer (TNBC) with a PARP inhibitor. O’Shaughnessy et al selected iniparib as the PARP inhibitor to study, and after a phase 2 study produced encouraging outcomes, she attempted to replicate them in an eagerly awaited phase 3 trial.¹ Expectations in the oncology community were high, and so, when the phase 3 results were poor, profound disappointment ensued. PARP inhibitors had been so thoroughly documented to reverse TNBC that these results stunned many. There was almost a sense that these phase 2 and phase 3 trials were simply necessary preludes to an inevitable ceremonial coronation of a winner, rather than empirical trials requiring rigor and assuming nothing but additional understanding of a highly complex disease state and equally complex pharmacologic class of agents for it. The need for an explanation of the failed phase 3 study was acute. It was not long in coming.

A pharmacologic fact lurking in the shadows of these 2 trials explained the problem and quickly restored confidence in PARP inhibitors for TNBC. As Metzger-Filho et al blandly state, “Iniparib (BSI-201) was initially thought to be a PARP inhibitor, but recent data indicate that iniparib does not possess characteristics typical of this class.”² In short, the trials were studying a drug that is not a PARP inhibitor.

Oops. Mistaking a drug’s class and function is not unprecedented – it has happened before. It tends to occur in new drug classes, reflecting the subtlety and the perils of cutting-edge research, which can become bleeding-edge research when any of the subtle pharmacologic qualities of the drug are overlooked. The good news is that it has not slowed work on several new PARP inhibitors. Had politics ruled medicine, the failed phase 3 trial would have consigned PARP inhibitors to the fast-fail drug heap, depriving TNBC patients of their best hope.

The issue involves the immense complexities of both PARP inhibitors and TNBC. Metzger-Filho et al provide a useful summary perspective of these conjoined issues:

TNBC is a challenging disease that has lacked a standardized treatment approach both in the early and advanced settings. Available evidence suggests that among patients with TNBC, prognosis seems to vary according to factors such as age and pathologic subtype. Several research groups have provided important insights into TNBC heterogeneity. Genes related to immune response have been shown to be of prognostic and predictive value, but validation is needed. PARP inhibitors have demonstrated impressive results in studies in the BRCA1/2 BC [breast cancer] subpopulation, but the identification of nonmutant TNBC likely to derive the same magnitude of benefit remains challenging. Prospective clinical trials coupled with integrated adequately powered translational research questions are likely to improve the outcome of patients with TNBC and should be our priority.²

Personalized medicine is a perfect model for understanding how to combat TNBC with PARP inhibitors. But like any recently understood disease entity, TNBC requires oncologists to go past the punch lines of clinical trials and understand its biology and a drug’s pharmacodynamics in minute detail. We are dealing with a heterogeneous disease state – a textbook environment for an iterative process of understanding diagnostic and treatment nuances: “The lack of a consensus definition for stratifying TNBCs into subtypes attests to the molecular complexity of basal tumors, underscoring the need for comprehensive translational research efforts in this field.”²

Just how heterogeneic is the disease that iniparib was sent out to treat? The overview by Metzger-Filho et al cuts to the chase with their article’s title: Dissecting the Heterogeneity of Triple-Negative Breast Cancer. It puts us on notice that this disease state is fiercely complex and has a lot of moving parts that cannot be oversimplified by clinician or researcher: “As the heterogeneity of TNBC is better defined, potential therapeutic targets are likely to emerge. A better understanding of the immune system is likely to foster new therapies designed to modulate immune response. For the time being, studies in TNBC are focused on evaluating the role of novel cytotoxics or available cytotoxics in combination with known target agents.”² A major consideration is patient selection: “In clinical practice, patients are selected for treatment based on clinical stage, tumor histology, and biomarkers with the ability to predict response to treatment.”² A heterogeneous disease state is a textbook environment for obstacles in attaining the precision in diagnostics and treatment. HER2 receptor assessment follows a standardized definition according to guidelines, but hormone receptor assessment varies across different countries, and different immunohistochemistry (IHC) cutoffs are used to define positivity. The American Society of Clinical Oncology/College of American Pathologists guidelines for IHC testing for estrogen receptors and progesterone receptors recommend that assays be considered positive if there is at least 1% of positive tumor cells in the sample.³ If this description connotes nothing else, it is the demand for attention to detail in high science.

So the oncologist treating TNBC must dig beneath the succinct definition of PARP inhibitors, neatly described as “…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.”⁴ They work in concert with conventional chemotherapy and radiation interventions that seek to break a tumor’s DNA double-strands. The body responds by attempting to repair the double-strand break that would kill the tumor cells, by “…a BRCA1/2-dependent, high-fidelity process in which the homologous sequence is used to precisely repair the break.”⁴ A definition is by no means a guide to treatment; the answers will lie in the details, and they are legion.

Translational research…personalized medicine depends on it, feeds on it, this intersection between research and clinical practice. O’Shaughnessy and colleagues did not dislodge research into PARP inhibitors, but if anything accelerated it by forcing a deeper look into the pharmacologic distinctions between iniparib and the real PARP inhibitors. The phase 3 research “failure” speaks to the need for cultivating a sense of what is on or off track in charting a treatment course in any newly delineated disease state – and TNBC is less than a decade old, PARP inhibitors younger.

Disappointment with clinical trial results also cultivates patience rather than a precipitous dismissal of new agents when survival is only nominally improved. We will examine this fascinating matter in our next column, for within it lays another component of personalized medicine: things are not always what they seem, and limited survival improvements may not always signal retreat. It involves the matter of proof of concept, and it is part of the exotic biological jungle we have entered when we accepted the challenge to confront cancer with personalized medicine.

References

1. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29(suppl). Abstract 1007.
   
2. Metzger-Filho O, Tutt A, de Azambuja E, et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol. 2012;30:1879-1887.
   
3. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784-2795.
   
4. Carey L, Sharpless N. PARP and cancer – if it’s broke, don’t fix it. N Engl J Med. 2011;364:277-279.

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