Johann de Bono
Drugs that inhibit the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) have been shown to be effective in treating ovarian, breast, and prostate cancers in patients with inherited BRCA mutations. In broadening the therapeutic scope of PARP inhibitors beyond germline BRCA-mutated cancers, research presented at the 2014 National Cancer Research Institute (NCRI) Cancer Conference in Liverpool (November 2-5) showed encouraging results for the anti-tumor activity of PARP inhibitors in sporadic castrate-resistant prostate cancer (CRPC).1
Johann de Bono, professor of experimental cancer therapeutics at the Institute for Cancer Research, London, presented data from the phase II trial TOPARP that assessed the antitumor activity of olaparib in patients with CRPC. An estimated 20% to 40% of patients have defects in DNA repair machinery that would render the tumors vulnerable to PARP inhibition by synthetic lethality.
Healthy cells have several mechanisms to maintain genome integrity, and these pathways are frequently dysregulated in cancer cells. Individuals with heterozygous mutations in BRCA1 or BRCA2 genes, which encode proteins responsible for DNA repair, have increased risk for developing breast, ovarian, prostate, and pancreatic cancers; BRCA1 or BRCA2 cells that have mutated to the homozygous state have faulty repair mechanisms and become cancerous.
De Bono and colleagues found that inhibiting an enzyme from a different DNA repair pathway cripples DNA maintenance to the point of chromatin instability, cell cycle arrest, and eventual apoptosis. The lethal double mutation, a situation termed synthetic lethality, presents the opportunity to target cancer cells, because the enzyme inhibition is only lethal in cells with existing DNA repair issues (ie, the cancer cells).
De Bono explains, “A major benefit of using PARP inhibitors is that they preferentially kill cancer cells while sparing normal cells, causing fewer side effects than traditional chemotherapies.” The European Medicines Agency recently recommended approval of olaparib (Lynparza) in platinum-sensitive, relapsed ovarian cancer as maintenance treatment for patients who are BRCApositive, based on phase II clinical trial results.2
Olaparib was shown to significantly prolong progression-free survival compared with placebo (11.2 months vs 4.3 months, P
<.0001). Adverse events were mild to moderate, including nausea, vomiting, fatigue, and anemia.
Several trials have shown the efficacy of PARP inhibitors in patients with BRCA mutations, but many cancers develop spontaneous abnormalities in the DNA repair pathways that create potential lethal interactions with PARP inhibitors. The TOPARP trial seeks to identify biomarkers that predict response to PARP inhibition in patients with CRPC. Initial results on 30 patients showed that olaparib was well tolerated and had a response rate of 33% (10/30 patients). Somatic cell exome and transcriptome analyses from tumor biopsies of respondents indicated loss of function of genes involved in DNA repair, including BRCA2.3
De Bono, J. DNA repair defects, PARP inhibitors and metastatic prostate cancer. Oral presentation at: National Cancer Research Institute Cancer Conference, 2014 Nov 2-5; Liverpool, UK. http://conference.ncri.org.uk/abstracts/2014/abstracts/para31.html. Accessed November 6, 2014.
AstraZeneca. Lynparza™ (olaparib) receives positive CHMP opinion in the EU for the maintenance treatment of BRCA-mutated platinum sensitive relapsed ovarian cancer. http://www.astrazeneca.com/Media/Press-releases/Article/20141024--lynparzaolaparib- receives-positive-chmp-opinion. Accessed November 6, 2014.
Mateo J, Hall E, Sandhu S, et al. Antitumour activity of the PARP inhibitor olaparib in unselected sporadic castration-resistant prostate cancer in the TOPARP trial. Ann Oncol. 2014; 25 (suppl4). http://annonc.oxfordjournals.org/content/25/suppl_4/mdu438.20. Accessed November 6, 2014.