Anticancer agents that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes have defined a new therapeutic paradigm known as synthetic lethality.
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).
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.
Among 136 serous ovarian cancer patients with deleterious BRCA1/2 mutations, olaparib conferred an 82% reduction in the risk of disease progression or death and a PFS benefit of more than seven months compared with placebo (11.2 vs 4.3; P <.00001). A strong trend for OS was also observed among mutation- positive patients, though this was not statistically significant. Another exploratory endpoint, PFS2, was also found to be significantly higher in olaparib- treated patients. PFS2 reflects the time between initiation of olaparib and disease progression on a subsequent therapy.
Olaparib would provide an important option for appropriate patients with ovarian cancer, noted Jane Robertson, MD, global product vice president at AstraZeneca, in an interview at ASCO. “Platinum-based chemotherapy can really only be given for a fixed number of cycles due to chemotactic toxicity, whereas olaparib is a well-tolerated oral agent but it’s still giving out a continued antitumor effect and can be carried on for much longer than conventional chemotherapy,” said Robertson.
AstraZeneca plans to proceed with two phase III trials assessing olaparib as maintenance therapy in patients with BRCA mutations who are either platinum- sensitive or high-risk patients following first-line chemotherapy. Their hope is that the observed improvements in PFS will be enough to gain approval for olaparib, and a marketing authorization application is already being prepared for the European market. The company also is seeking a Breakthrough Therapy designation from the FDA.
Olaparib is being evaluated in a number of other patient populations for which positive results were also reported at the ASCO meeting. A randomized, double- blind, phase II study examined the efficacy of a combination of olaparib and the chemotherapeutic agent paclitaxel in patients with metastatic or recurrent gastric cancer. The study was enriched for patients with tumors expressing low levels of the ataxia telangiectasia mutated (ATM) kinase, which is involved in DNA repair, after preclinical findings suggested that low levels of this protein were associated with sensitivity to olaparib. The combination was found to be well tolerated, and a statistically significant improvement in OS was observed, with the greatest benefit among patients with low ATM tumors (NCT01063517).
Another study is examining whether advanced tumors with BRCA1/2 mutations are responsive to olaparib regardless of tumor type. Antitumor activity was observed in pancreatic and prostate cancer patients, among others, and was well tolerated (NCT01078662).
The epidermal growth factor receptor (EGFR) and phosphatidylinositol-3-kinase (PI3K) pathways have been implicated in the repair of DSBs and, as such, provide potential strategies for inducing synthetic lethality in combination with PARP inhibitors. Olaparib is being evaluated in a phase I trial in combination with the EGFR inhibitor gefitinib in EGFR-mutant patients with advanced non-small cell lung cancer (NSCLC) and has demonstrated activity (stable disease in >40% of patients) and tolerability (NCT01513174). A phase II trial is planned for 2013.Rucaparib (CO-338, formerly PF 01367338 or AGO14699) was actually the first PARP inhibitor to enter clinical trials, but is lagging behind olaparib somewhat in its development. The results of two phase I trials in patients with advanced solid tumors were presented at ASCO this year (NCT01009190, NCT01482715). A combination of rucaparib and the platinum-based chemotherapy agent carboplatin demonstrated activity at clinically relevant doses of each agent and was well tolerated, while continuous oral administration of rucaparib as monotherapy also showed encouraging clinical activity and tolerability. In the former trial, the overall disease control rate across all doses was 50%, while in the latter trial objective responses and durable stable disease were observed. Treatment-related adverse events included nausea and fatigue in both trials.
A preclinical trial indicated that combining rucaparib with an inhibitor of PI3K was effective in breast cancer cell lines, again suggesting this combination is a potentially viable route to synthetic lethality. Rucaparib is currently being evaluated in phase II clinical trials in ovarian and breast cancer (NCT01891344, NCT01482715, NCT00664781).Veliparib (ABT-888) is currently undergoing phase I and II clinical testing for a variety of indications, including ovarian, breast, and pancreatic cancer, and acute leukemia (NCT01012817, NCT01149083, NCT01489865, NCT01139970). Several studies presented at ASCO focused on the combination of veliparib with carboplatin. George Somlo, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, presented data from a phase II trial of this combination in patients with BRCA-mutant breast cancer. Significant response rates were observed, with a clinical benefit rate greater than 70%. This activity came at the expense of increased hematologic toxicity, although this was manageable.
Furthermore, this study indicated that continuous exposure to veliparib in this combination was feasible, while other abstracts presented at ASCO showed that intermittent dosing was required for olaparib and rucaparib in combination with carboplatin. In a separate presentation reviewing these data, Andrew Tutt, MB ChB, PhD, professor of Oncology at King’s College London, suggested that this may reflect differences in the relative activity of the various PARP inhibitors on suppression of PARP catalytic activity and PARP trapping.
Results from a phase I trial of veliparib in combination with temozolomide in pediatric patients with recurrent central nervous system tumors were also discussed (NCT00946335). The combination showed significant activity, was well tolerated, and had pharmacokinetic parameters similar to those observed in adults. A phase II trial is planned.A single study of niraparib (MK4827) was presented at ASCO, which discussed the final results of a phase I trial in BRCA mutation carriers with sporadic ovarian cancer, and castration-resistant prostate cancer. One hundred patients received niraparib at a variety of dose levels. It was well tolerated and showed promising antitumor activity, with RECIST and/or cancer antigen 125 (CA125) partial response rates up to 50%. Among patients with high-grade serous ovarian cancer, those with platinum-sensitive disease and BRCA mutations had higher response rates.BMN 673 is the most potent and specific PARP inhibitor in development (with an IC50<1nM). Johann de Bono, MD, PhD, professor of Experimental Cancer Medicine at the Institute of Cancer Research, London, described the results of the first-in-human trial of BMN 673 in patients with solid tumors (NCT01286987). It demonstrated impressive antitumor activity as a single agent, with Response Evaluation Criteria in Solid Tumors (RECIST) or CA125 responses occurring in almost 65% of patients with BRCA-mutant ovarian/peritoneal cancer and more than 30% of patients with BRCA-mutant breast cancer.Two other PARP inhibitors are currently in clinical development. Eisai Inc is sponsoring a small phase II trial into the combination of the PARP inhibitor E7016 with temozolomide in patients with wild-type BRAF stage IV or unresectable stage III melanoma (NCT016052). Cephalon, now part of Teva Pharmaceutical Industries, is investigating CEP-9722, a small pro-drug of CEP-8983 that inhibits PARP-1 and PARP-2, in a phase I/II trials for solid tumors (NCT01311713).
PARP Inhibitor (Company)
Stage (Abstract No)
Phase II retrospective
BRCA-mutated serous ovarian cancer; platinum-sensitive disease
Metastatic/recurrent gastric cancer
Breast and ovarian cancer; BRCA1/2 mutation carriers
Heavily treated patients with advanced cancer; BRCA1/2 mutation carriers
Advanced NSCLC; EGFR mutation carriers
Pediatric central nervous system tumors
Metastatic breast cancer; BRCA1/2 mutation carriers
Pediatric central nervous system tumors
Advanced solid tumors
Heavily treated advanced solid tumors
Advanced solid tumors
Advanced solid tumors; BRCA mutation carriers
Sources: Abstracts, posters, and oral presentations from the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. Available at http://meetinglibrary.asco.org.
aDisease control rate is defined as CR + PR + SD.
bCBR is defined as CR, PR, or SD.
ATM indicates ataxia telangiectasia mutated; BID, twice a day; CBR, clinical benefit rate; CRPC, castration-resistant prostate cancer; CR, complete response; FOXO3, forkhead box 03; NSCLC, non-small cell lung cancer; NFκB1, nuclear factor kappa B1; OS, overall survival; PFS, progression-free survival; PR, partial response; QD, every day; RECIST, Response Evaluation Criteria in Solid Tumors; RR, response rate; SD, stable disease; TDS, three times a day.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.
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