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PROfound trial

ESMO 2019: Targeted therapy slows progression of advanced prostate cancer

Therapy with the PARP inhibitor olaparib delayed cancer progression in patients with metastatic, pre-treated prostate cancer with loss-of-function alterations in HRR genes by about four months compared to new hormonal agents (enzalutamide or abiraterone acetate).1

In the PROfound trial, two groups of patients were included: one group of men with BRCA1, BRCA2 and ATM mutations and a second group with a broader range of less well studied faulty DNA repair genes. All included patients were pretreated. Olaparib was thereby compared with new hormonal agents agents (enzalutamide or abiraterone acetate).

In the first cohort, median progression-free survival was 7.39 vs. 3.55 months of olaparib compared to new hormonal treatments (HR 0.34, p<0.0001).
Interim analysis for overall survival (OS) for the first cohort showed a median OS of 18.5 months with olaparib compared to 15.11 with hormonal treatment (HR 0.64, p=0.0173), while these results were still immature. Median OS in the overall population was 17.51 vs 14.26 months (HR 0.67, p=0.0063 [nominal]) with olaparib vs hormonal treatment respectively.
Adverse events were more common with olaparib than with hormonal treatment, though median treatment duration was longer with olaparib (7.4 months) than hormone treatment (3.9 months). In the olaparib group, 16.4% of patients discontinued treatment due to adverse events, compared to 8.5% with hormonal treatment.

Benefit in all subgroups

“To see such a significant effect on disease progression and other clinically relevant effects such as pain progression and objective response rate is a remarkable achievement in such heavily pre-treated patients with prostate cancer,» said study author Prof Maha Hussain, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA. «We saw the benefits of olaparib in all subgroups of patients, regardless of country, age, prior therapy and severity of disease, including those with worse disease that had spread to their liver or lungs,» Hussain pointed out.

Commenting on the data, Dr Eleni Efstathiou, MD Anderson Cancer Center, Houston, USA, said: «This is a landmark trial as it is the first phase III trial looking specifically at tumors harboring a targetable molecular alteration. In patients with such tumors, treatment with olaparib resulted in a 66% greater delay in progression than the new hormonal agents which were used in PROfound. This is impressive because it is considerably higher than the 35–40% improvements with which we’ve been very satisfied in previous prostate cancer studies in this more advanced disease setting. There is a trend towards improved survival, but we need to wait for the final analysis.» She added, «We should not ignore that significant adverse events, such as anemia and nausea, were more common with olaparib as these can have an important effect on a patient’s ability to take the drug. In practice, patients will need to be carefully monitored.»

References

1 Hussain M et al. PROFOUND: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (MCRPC) with homologous recombination repair (HRR) gene alterations. LBA12_PR

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