Anticancer agents that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes have defined a new therapeutic paradigm known as synthetic lethality
. Since the 1980s, substantial efforts have been focused on the design and development of these agents, resulting in a number of promising compounds entering clinical trials. However, there are currently no FDA-approved PARP inhibitors, and the road to approval has been a bumpy one, paved with some disappointment.
The 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago saw the resurrection of one PARP inhibitor and a wealth of positive clinical trial data from several others, which reflects a greater understanding of PARP biology and the patient populations who would benefit most from their use. Here, we summarize the research presented at the ASCO meeting that highlight the ongoing story of PARP inhibitors in oncology (see table on page 3
How PARP Inhibitors Work
The PARPs are a family of multifunctional enzymes that catalyze the ADP-ribosylation of target proteins. Essentially, this involves the addition of bulky, charged molecules onto these target proteins, which interferes with their function and interaction with other proteins. PARP-1 and PARP-2, the most fully studied members of the family, have as one of their key functions the repair of damaged DNA.
DNA can be damaged as a result of environmental exposure (eg, ultraviolet radiation from the sun) or through errors introduced during its replication. Cells have a number of different mechanisms that allow them to repair damaged DNA, which include base excision repair (BER), nucleotide excision repair, homologous recombination (HR), and non-homologous end-joining (NHEJ). The PARPs have a particularly critical role in the BER pathway, binding to single-strand breaks (SSBs) in DNA, modifying proteins in the vicinity, and ultimately leading to the recruitment of DNA repair proteins to the sites of damage.
PARP inhibitors block the activity of the PARP enzymes by mimicking the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) and binding to thePARP catalytic site, which either directly blocks PARP enzymatic activity or causes PARP to accumulate on DNA (known as PARP trapping
). One downside to this mechanism of action of current PARP inhibitors is that they are broad spectrum and target not just PARP-1 and PARP-2, but other members of the PARP family.
PARP inhibitors are the poster child for the therapeutic paradigm of synthetic lethality in cancer drug development, the theory that two defects which alone are benign in cancer cells, can be lethal when combined. If SSBs are left unrepaired, they have the potential to develop into lethal double-strand breaks (DSBs), which would lead to cell death. Suppressing PARP activity prevents SSB repair via the BER pathway, but other DNA repair pathways such as HR and NHEJ simply take over. However, if PARP inhibitors are used against tumors in which there is already a DNA repair defect, the combination drives synthetic lethality.
There are two routes to synthetic lethality with PARP inhibitors. They can be used as monotherapy in patients with known mutations in DNA repair proteins, the most renowned being the breast cancer type 1 and 2 susceptibility proteins (BRCA1 and BRCA2), or they can be used as combination therapy with DNA-damaging chemotherapeutic agents or radiotherapy.
At least seven agents are in various stages of development. Rucaparib was first to enter clinical trials, but olaparib is now the most advanced. Iniparib was previously classed as a PARP inhibitor but development was terminated after it proved not to be a bona fide inhibitor of PARP and displayed poor clinical activity in phase III trials.
In clinical trials, PARP inhibitors are generally described as well tolerated with manageable toxicities. Low-grade fatigue and nausea are the most commonly reported adverse events, while more serious toxicities such as myelosuppression, particularly thrombocytopenia, have been observed for several agents used in combination with chemotherapies.
Olaparib (AZD-2281) was previously under development for patients with serous ovarian cancer and showed a promising progression-free survival (PFS) benefit in this population. However, in late 2011, AstraZeneca announced that it was halting development of olaparib after an interim analysis suggested that this PFS benefit was unlikely to translate into an overall survival (OS) benefit— the key to securing FDA approval.
In April 2013, however, AstraZeneca declared that the company would be pushing this agent forward into phase III trials in patients with deleterious BRCA1/2
mutations, following a retrospective analysis of this subset of patients. Jonathan A. Ledermann, BSc, MD, FRCP, professor of Medical Oncology at University College London, presented the phase II results, which prompted this U-turn, at this year’s ASCO meeting.