ESMO 2019: Invited Discussant - PROfound: A Phase 3 Study of Olaparib versus Enzalutamide or Abiraterone for mCRPC with Homologous Recombination Repair Gene Alterations

Barcelona, Spain (UroToday.com) Following oral presentation of the PROfound study of olaparib in metastatic castration-resistant prostate cancer (mCRPC) patients with selected homologous recombination repair defects in their tumors, Dr. Eleni Efstathiou discussed the findings and posed the question of whether this study should be considered practice-changing.


The discussant outlined her requirements for a study to be truly practice-changing:

  • It must address an unmet need
  • The experimental arm must be compared to standard of care
  • A positive outcome must be clinically meaningful
  • Results must be reproducible – not possible yet for this trial as it is the first
  • The proposed practice change must be accessible to the community

Regarding unmet need, it is clear that patients with germline alterations in DNA damage repair, especially BRCA2, have worse outcomes and respond poorly to cytotoxic therapies. It is not entirely clear that this can be extended to somatic mutations, though a recent publication showed that pathogenic germline and somatic alterations in this pathway occur with equal frequency in prostate cancers1. Interestingly, biallelic somatic loss of BRCA2 may not be required to sensitize patients to PARP inhibition, though this has not been shown prospectively. Regardless of the prognosis or predictive deleterious effect of DNA damage repair defects, it is clear from this presentation and others that molecularly guided therapies represent an overall unmet need in mCRPC.

Though sequential therapies with anti-androgens does not have clear benefit, the design used in this trial of comparing olaparib to whichever of abiraterone or enzalutamide had not been used previously does represent current standard practice. Importantly, patients were able to crossover to olaparib upon progression. The Kaplan-Meier curves from the presentation clearly show that crossover happened quickly, with 70% of patients progressing radiographically by four months.

Can the proposed change in standard of care be accessed by the community? Dr. Efstathiou thinks yes. The genomic test used to identify DNA repair defect is a slight modification to a widely commercially available test. The patients treated in this trial represent real-world patients. There is likely, however, to be a significant learning curve in the treatment community as physicians become accustomed to using PARP inhibitors in prostate cancer, and become more comfortable with using and interpreting genomic assays for determining therapy in prostate cancer.

Ultimately, based on this discussion, Dr. Efstathiou believes that the data in PROfound is truly practice changing and represents a major step forward in the molecular biomarker-driven care of patients with mCRPC. Similarly to other recently approved mCRPC drugs, further studies will likely examine whether olaparib therapy can be moved forward in the disease course of a patient in order to further improve their outcome. 

Clinical Trial Information: NCT02987543


Reference:

1. Jonsson, Philip et al. 2019. "Tumour lineage shapes BRCA-mediated phenotypes". Nature 571 (7766): 576-579. Springer Science and Business Media LLC. doi:10.1038/s41586-019-1382-1.

Presented by: Eleni Efstathiou, MD, Ph.D., Associate Professor in the Department of Genitourinary Medical Oncology at the MD Anderson Cancer Center, Houston, TX, USA

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

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