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Olaparib in combination with Abiraterone delays disease progression in metastatic castration-resistant prostate cancer


Data, presented at 2018 American Society of Clinical Oncology ( ASCO ) Annual Meeting, showed clinical improvement in median radiologic progression-free survival ( rPFS ) with Olaparib ( Lynparza ) in combination with Abiraterone compared to Abiraterone monotherapy, a standard of care, in metastatic castration-resistant prostate cancer ( mCRPC ).

The results of Study 08, a randomised, double-blinded, multi-centre phase II trial, comparing Olaparib in combination with Abiraterone ( n=71 ) to Abiraterone monotherapy ( n=71 ) in patients with previously-treated mCRPC, regardless of homologous recombination repair ( HRR ) mutation status.

The primary endpoint was rPFS. Secondary endpoints included time to second progression or death ( PFS2 ), overall survival ( OS ) and health-related quality of life.

A previous trial demonstrated improvements in response rates with Olaparib monotherapy in metastatic castration-resistant patients with HRR mutations.
The Study 08 combination data suggests that regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from Olaparib in combination with Abiraterone.

Median rPFS was 13.8 months with Olaparib and Abiraterone compared to 8.2 months with Abiraterone alone ( hazard ratio, HR=0.65; 95% CI 0.44-0.97; p=0.034 ).
Median PFS2 was 23.3 months vs 18.5 months ( HR=0.79; 95% CI 0.51–1.21 ).
Median OS was 22.7 months with combination treatment versus 20.9 months with Abiraterone alone ( HR=0.91; 95% CI 0.60–1.38 ).
Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients, regardless of HRR status.

Study 08 was not powered for subgroup analyses, PFS2 and OS.

The safety profile of Olaparib and Abiraterone was generally manageable, with no detrimental effect on quality of life compared to Abiraterone alone.
Grade greater than or equal to 3 adverse events, serious adverse events and treatment discontinuations due to adverse events were more frequent with combination treatment than Abiraterone alone ( 54% and 28%; 34% and 18%; 30% and 10%, respectively ).
The most common grade greater than or equal to 3 adverse events in the combination arm were anaemia ( 21% ), pneumonia ( 6% ) and myocardial infarction ( 6% ).
Serious cardiovascular events occurred in seven patients in the combination group and one patient in the Abiraterone group.

Olaparib was the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response ( DDR ) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Olaparib-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate.
Development of prostate cancer is often driven by male sex hormones, androgens, including testosterone.
mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.
Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.
Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.
Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28%. ( Xagena )

Fonte: AstraZeneca, 2018

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