Emergence of True "Individualized" Therapy: The PARP Inhibitors
Emergence of True "Individualized" Therapy: The PARP Inhibitors
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a retained consultant to GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureaus for GlaxoSmithKline, Eli Lilly Co., and OrthoBiotech.
Synopsis: The BRCA genes function as tumor suppressors and perform an important role in DNA repair. Women and men who harbor germline mutations in these genes are at increased lifetime risk for a number of cancers, including breast, ovarian, and prostate cancers. The recently identified susceptibility of tumors to inhibition of PARP, a single-strand DNA repair enzyme, opens a new chapter in cancer therapeutics. This phase I trial provides the first "proof-of-principle" of this strategy in the clinic.
Source: Fong PC, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009 Jun 24; Epub ahead of print.
Preclinical data recently demonstrated the extreme sensitivity of BRCA-deficient cells to inhibition of the single-strand repair enzyme poly(ADP-ribose) polymerase (PARP). Inhibition of the PARPs leads to an accumulation of single-strand DNA breaks, which can lead to double-strand breaks at replication forks. Normally, these breaks are repaired through homologous recombination of which the BRCA genes play a major role. However, "synthetic lethality" occurs when these genes themselves improperly function due to mutation or silencing. This prompted the clinical development of a new class of novel therapeutic, the PARP inhibitor, which theoretically holds promise in patients whose tumors rely on this pathway for continued cell growth.
To test this hypothesis and to evaluate the safety of the first drug in this class, olaparib, a phase I, dose-escalation clinical trial was conducted to examine the pharmacokinetic and pharmacodynamic effects in patients with cancers refractory to standard therapy. Given the mechanism of action of olaparib, the population was enriched for patients with BRCA1 or BRCA2 mutations. Overall, 60 patients were recruited to the trial, including 22 who carried a BRCA1 or BRCA2 mutation and one with a strong family history of BRCA-related cancer. The dose of olaparib ranged from 10 mg daily, administered 2 of 3 weeks to 600 mg twice daily, continuously. At the two highest dose levels, dose-limiting toxicities were observed. This led to a compromised dose of 200 mg twice daily, which was studied in a second cohort of BRCA1 and BRCA2 patients only. In general, the agent was well tolerated with primary toxicities of somnolence, mood alteration, and fatigue. The toxicity profile was not increased in the BRCA subpopulation. Analysis of PARP function by pharmacodynamic studies demonstrated rapid and high level inhibition within the recommended dosing levels. In support of the hypothesis, objective antitumor activity (63% complete or partial response plus stable disease) was seen only in BRCA mutation carriers. Olaparib has few side effects relative to conventional chemotherapy, inhibits PARP, and has antitumor activity only in patients with BRCA germline mutation.
Commentary
Conceptually, the idea of identifying the right patient for the right treatment that has the best chance to impact an individual tumor is easy to understand and certainly appealing from both an efficacy and toxicity point of view. However, as the complexity of carcinogenesis becomes clearer, individualized therapy in this regard looms as a light at the end of the tunnel that never seems to brighten. The current report is certainly one clear exception — on many levels. First, it follows from a significant preclinical discovery and leverages the very genetic defect that predisposes to cancer in the first place, for a highly specific anticancer therapy. Second, the presence of a functioning BRCA gene in normal tissues affords a heightened therapeutic index, promoting tumor selectivity and low toxicity. Third, the level of "target engagement" or PARP inhibition, is high with rapid onset, even at low doses. Elimination is also rapid and predictable, making the agent clinically savvy. Based on these observations and findings, a new crop of PARP inhibitors is being introduced into the clinic in hopes of extending the beneficiary population. Indeed, it has been identified that somatic (or acquired) mutation in tumors may behave with a certain BRCA-ness, which could make them vulnerable to this type of intervention. Further, combination therapy of PARP inhibitors with chemotherapy was recently reported to be more beneficial than chemotherapy alone in unselected patients with metastatic, triple-negative breast cancer. While these latter two strategies may not prove clinically viable in the long run, it is clear that for the 10-15% of ovarian cancer patients who carry a BRCA mutation, truly individualized therapy is closer than ever imagined.
Suggested Readings
- De Soto JA, Deng CX. PARP-1 inhibitors: Are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers? Int J Med Sci 2006;3:117-123.
- Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008;451:1111-1115.
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921.
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