Adding the poly ADP ribose polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) to the androgen synthesis inhibitor abiraterone acetate (Zytiga, Janssen) significantly improves progression-free survival (PFS) in men with advanced prostate cancer over abiraterone alone, UK researchers have discovered.
Studying 142 patients with metastatic castration-resistant prostate cancer (mCRPC), Dr Noel Clarke, The Christie and Salford Royal Hospitals, Manchester, found that those given the combination were 35% less likely to experience progression than those given just abiraterone, although there was no overall survival benefit.
Interestingly, the improvement in PFS with combination therapy was seen regardless of whether or not the patients had homologous recombinant repair (HRR) gene mutations, which have been identified as a key potential mechanism of action for PARP inhibitors.
The new data were presented here at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. The study was also simultaneously published in The Lancet Oncology.
‘Significant Radiological Progression-Free Survival Benefit’
Clarke told the audience: “What we have shown in our study is that olaparib plus abiraterone provided a significant radiological progression-free survival benefit to mCRPC patents who had previously received docetaxel [Taxotere, Sanofi-Aventis] compared with abiraterone alone.”
While Clarke acknowledged that the benefit came at the expense of “an increased incidence of adverse events compared with abiraterone alone, particularly cardiac events”, he said that, based on their findings, the group has planned a phase 3 trial to test the combination further.
In an editorial accompanying the paper, Dr Emmanuel Antonarakis, from the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore in the US, questioned, however, the way in which HRR status was defined in the study, and that it was underpowered to detect a difference based on HRR status.
“Clarke and colleagues’ study certainly provides the impetus to explore this intriguing possibility further.”
Moreover, the low prevalence of mutations they detected, at 15%, suggests either that mutations were missed or that the men were potentially “homologous repair proficient”.
He notes that there are numerous potential explanations for the “seemingly paradoxical results” seen in the study, but that “clearly, larger prospective and biomarker-stratified randomised trials are needed” to test the notion of synergy between the two drugs.
Clarke began his presentation by noting that PARP inhibition plays an important role in blocking DNA repair pathways in cells that harbour HRR defects.
He said that there is also evidence that the combination of PARP inhibition and abiraterone works in a synergistic manner, with PARP involved in androgen-receptor dependent transcription and abiraterone inducing HRR deficiency.
–GDMeds, an India Pharmacy Service company
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