Olaparib has clinical efficacy in men with metastatic castration-resistant prostate cancer
medwireNews: Addition of olaparib to abiraterone is associated with increased radiographic progression-free survival (rPFS) in unselected patients with metastatic castration-resistant prostate cancer, show study findings.
“Our data suggest that the combination of olaparib and abiraterone has the potential to provide additional and practice-changing therapeutic options for men with metastatic castration-resistant prostate cancer,” the researchers write in The Lancet Oncology.
The phase III trial, which was simultaneously presented at the ASCO Annual Meeting 2018 in Chicago, Illinois, USA, showed that men treated with the PARP inhibitor olaparib 300 mg twice daily plus abiraterone had a significant 35% reduced risk for rPFS, compared with those treated with placebo plus abiraterone, at a median of 13.8 and 8.2 months, respectively.
The study was conducted at 41 sites across Europe and North America, and enrolled 71 men into each arm. Participants had previously received docetaxel and were enrolled irrespective of their homologous recombination repair (HRR) mutation status, All participants received oral abiraterone (1000 mg/day) and either prednisone or prednisolone (5 mg twice daily).
Noel Clarke (Christie NHS Foundation Trust, Manchester, UK) and colleagues comment: “To our knowledge, this is the first study of a PARP inhibitor to show a clinical benefit when combined with abiraterone for patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.”
Grade 3 or worse adverse events were more common in the olaparib group than the placebo group, at 54% versus 28%. These included anemia (21 vs 0%), pneumonia (6 vs 4%), and myocardial infarction (6 vs 0%). In addition, serious adverse events occurred in 34% of patients in the olaparib arm versus 18% of those in the placebo group.
The researchers note, however, that an “increased duration of exposure in the olaparib and abiraterone group suggests that this tolerability risk might be offset by the observed efficacy benefit,” adding that there were no differences in health-related quality of life between the two groups.
Although the study was not powered for subgroup analyses, a predefined exploratory analysis indicated a similar benefit for olaparib regardless of HRR mutation status, with a median rPFS of 17.8 months among 11 participants with mutated HRR and 15.0 months among 15 men with wild-type HRR.
This suggests that the treatment “could provide clinical benefit for a broader patient population,” notes the team.
In an accompanying commentary, Emmanuel Antonarakis (Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland, USA) hypothesizes that combining androgen receptor-targeted therapy with PARP1-targeted therapy may result in a “a new type of synthetic lethality”.
Although larger prospective trials with biomarker stratification are needed to test this idea, Antonarakis notes that “Clarke and colleagues’ study certainly provides the impetus to explore this intriguing possibility further.”
By Catherine Booth
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