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

Robert E. Henry

The Last Word

The proposition appeared simple – as it turns out, deceptively so. The oncology community was a bit disheartened when the much anticipated results of a phase 3 trial by Dr Joyce O’Shaughnessy did not replicate the success of her phase 2 study1 in which the PARP inhibitor iniparib was used in combination with chemotherapy, resulting in improved outcomes for women with metastatic triple- negative breast cancer. Hopes for the phase 3 study were high since PARP inhibitors are especially well suited for victims of this lethal form of breast cancer.

It is useful to call to mind that this is personalized medicine we are dealing with: the up-close-and-personal exploration of the mechanics of tumor DNA destruction and the body’s vast arsenal of enzyme wizardry trying its best to repair broken single and double strands of DNA. Cancer revolves around nature’s misguided attempt to protect damaged DNA and prevent cell death – even the cell death of the body’s worst enemy. So it is somewhat naive to elevate hopes to expectations at this early stage of research of this young class of agents in an equally young category of breast cancer. How young? “A PubMed search of the medical literature shows that the first mention of ‘triple-negative’ breast cancer was in October 2005.”2 Dig a little deeper and we discover that “Many cancers meet the definitions of both triple-negative breast cancers and basal-like breast cancers.”2 In fact, experts for a time claimed that triple-negative cancers and basal-like phenotypes are basically identical,3,4 but this was overturned: “…clinical, microarray, and immunohistochemical data show that this is not the case.”2 Similarly, PARP inhibitors had only begun to show up in clinical trials around 2009,5 and Foulkes and colleagues join the ranks of researchers who regard them as our best hope for triple-negative breast cancer: “PARP inhibitors and other targeted agents are now at the forefront of clinical research on the treatment of triple-negative breast cancer.”2

Alright…let’s try to connect some of the dots. First of all, patience rather than dismay might be a more reasonable response to the inconsistent outcomes here. We are not in a state of disarray because the outcomes of the first study were not replicated in the next one. The reason may involve a stunning, singularly humbling statement that we find in the conclusion of Foulkes’ article. At the end of his brilliant coverage of the forces in play in triple-negative breast cancer, he mentions a pathophysiologic fact of staggering significance almost as an aside. Triple-negative breast cancer and its symptomatically look-alike disease state, basal-like breast cancers, have been keeping a secret from patients, researchers, oncologists, payers, and pharmaceutical companies seeking to distill a cure. To wit: each of these disease states are probably not “…single entities but rather are a collection of different diseases. Hence, studies that address the molecular underpinning of this heterogeneity and attempt to identify the drivers of therapeutically relevant subgroups of triple-negative and basal-like breast cancers are warranted.”2,6 Now that is worth a double take. We’ve been given a clue worth following up in our search for the slip twixt phases 2 and 3 trials of the PARP inhibitor – which has been sent out on the mission to combat one disease state, only to find a cluster of them, each with its own pathophysiologic actions. Imagine the possibilities, the detours awaiting the PARP inhibitor as it wends its way through a cluster of diseases. So perhaps the faith placed in PARP inhibitors is not misplaced after all, when what we are facing is a far more complex entity than anticipated. And so, expectations for pinpoint accuracy in back-to-back trials treating a disease state that isn’t a single disease are seen to be premature at best. We have much to learn, and there is no reason to think we are on the wrong track using PARP inhibitors. More likely we are facing a situation of finding the specific patient subset that will be responsive to them. More tests, please.

The O’Shaughnessy phase 3 study holds a meaningful lesson for all involved in personalized medicine’s targeted approach to cancer treatment. There is value in looking beyond the empirical results of trials. A careful examination of the designs of each study is in order to learn if differences in method account for the different results. Assumptions of PARP inhibitor ineffectiveness are unwarranted, and expectations should be replaced by patient review of results. This “failure” is really just a signpost on a road that may lead to successful use of PARP inhibitors. It suggests a need for becoming familiar with the biological mechanics of triple-negative breast cancer and the pharmacodynamics of this new targeted therapy for it. This column has not yet touched on the nuances of PARP inhibitors – which make fascinating reading in themselves, to be sure! Space prohibits doing justice to them and explaining why they are being studied so vigorously.

Our next column will focus on triple-negative breast cancer’s multifaceted disease state and discuss the specifics of PARP inhibitors, the unofficial drug of choice for this unconventional disease state. Suffice it for now to say that this confidence appears valid – odd as it may seem to place confidence in anything involved in this cutting-edge field of diagnosis and treatment. There is substantial cause for hope for this class of drugs in triple-negative breast cancer, once we reexamine the clinical trial designs employed. As promised, specifics concerning this drug class shall occupy our energies in the next column.

A closing sentiment involves a statement delivered at a news conference years ago by Dr John Henry Laragh, the researcher credited with discovering the renin-angiotensin-aldosterone hormonal control system as the basis for hypertension. Extrapolate his point of reference a bit, and the relevance of his wisdom to the current matter becomes clear: “Risk factors are indicative of our ignorance, not our knowledge. A disease has one cause, not several. Thus, if we knew the cause of the disease, we would not be exploring multiple risk factors, only the one producing the condition. But we do not possess that knowledge, and so we cast a wide net. Let us therefore advance our propositions with intellectual humility and remain open to alternative schools of thought.”

The more things change, the more they remain the same. Personalized medicine is just our new medicine. As with all medical advancement, it should be approached with caution and intellectual humility, not assumptions of success, following Dr Laragh’s refreshing advice. We do better to make use of emerging research, learning continually about the biological basis of cancers, and maintaining composure when results depart from expectations as we endeavor to heal with new personalized medicine techniques and drugs. Patients deserve our diligence and humility – a rational and productive package. So before expressing dismay over the first disappointing study on PARPs, we may also want to consider advice offered in The Hitchhiker’s Guide to the Galaxy…“Don’t Panic!” Personalized medicine, after all, is quite a big galaxy.

Robert E. Henry

References
1. O’Shaughnessy J, Osborne C, Pippen JE, et al, Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-214.
2. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
3. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800.
4. Kreike B, van Kouwenhove M, Horlings H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9:R65.
5. Alli E, Sharma VB, Sunderesakumar P, et al. Defective repair of oxidative DNA damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase. Cancer Res. 2009;69:3589-3596.
6. Ossovskaya V, Li L, Broude EV, et al. BSI-201 enhances the activity of multiple classes of cytotoxic agents and irradiation in triple negative breast cancer. In: Program and abstracts of the American Association for Cancer Research Annual Meeting; April 18-22, 2009; Denver, CO. Abstract 5552.

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