Olaparib as a new standard of care in castration-resistant prostate cancer

December 2020 Clinical Practice Tobias Rawson

Published in the New England Journal of Medicine, the phase III PROfound study has concluded that olaparib offers a superior overall survival (OS) benefit in men with castration-resistant prostate cancer (CRPC) expressing a mutation in the genes BRCA1, BRCA2 or ATM, which has progressed during treatment with a next-generation hormonal agent, compared to a physician’s choice of enzalutamide or abiraterone, plus prednisolone. 

Key findings

With similar, previously published findings in progression-free survival (PFS), in which olaparib conveyed a median PFS of 7.39 months, compared to 3.55 months on the physician’s choice (HR[95%CI]: 0.34[0.25-0.47], P< 0.0001), at this updated final analysis, olaparib was found to produce a median OS of 19.1 months, compared to the physician’s choice, which conveyed a survival of 14.7 months (HR[95%CI]: 0.69[0.50-0.97], P= 0.02). These conclusive results were further supported by the finding that over 60% of control patients crossed-over to receive olaparib, following disease-progression, and that time to second disease progression was 15.5 months versus 10.6 months, respectively (HR[95%CI]: 0.64[0.45-0.93]), suggesting a clear, realistic clinical benefit for the patient.

Study details

The phase III PROfound study is an open-label trial designed to assess the efficacy and safety of olaparib, compared to enzalutamide or abiraterone, plus prednisolone in progressive CRPC that exhibit mutations in homologous recombination repair genes. Stratified into two cohorts based on mutational status(Cohort A [N= 245]: BRCA1, BRCA2, ATM; Cohort B[N=142]:  BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) and randomised 2:1, 387 patients were enrolled to receive olaparib 300mg twice daily, or the physician’s choice of either enzalutamide 160mg once daily or abiraterone 1000mg daily, plus prednisolone 5mg twice daily. In this final OS analysis, the key secondary endpoint was median OS in cohort A.

Conclusion

The investigators conclude that “Among men with metastatic castration-resistant prostate cancer who had tumours with at least one alteration in BRCA1, BRCA2 or ATM, and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib.” As of 2018, 9,800 cases of prostate cancer are diagnosed every year in Belgium, with 1,654 presenting as stage III at time of diagnosis. Data, such as that obtained from the PROfound study, provide insight into how a personalised medical approach can be adapted to clinical practice, allowing physicians globally to make better, more informed clinical decisions that will ultimately benefit the patient.

References

Maha Hussain, M.D., Joaquin Mateo, M.D., Karim Fizazi, M.D et al., Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer, December 10, 2020, N Engl J Med 2020; 383:2345-2357, doi: 10.1056/NEJMoa2022485

M. Hussain, J. Mateo, K. Fizazi et al., PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations, as presented at ESMO october 2019.

Fact sheet on prostate cancer from the Belgian national cancer register.

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