Diagnostic Test Brings a Precision Medicine Approach to Prostate Cancer Drug

A collaborative study among scientists working across 3 continents has found a strong association between circulating free DNA (cfDNA) in patients being treated with olaparib (Lynparza) for prostate cancer and disease outcome. These results confirm a prognostic role for cfDNA in prostate cancer.

Olaparib (Lynparza) is a poly-ADP ribose polymerase (PARP) inhibitor that has been approved for treating BRCA1/2-mutated advanced ovarian cancer. Late-stage studies with the drug have seen also improved outcomes in breast cancer. With defects also seen in the PARP DNA repair enzyme observed in prostate cancer, the TOPARP-A (Trial of PARP Inhibition in Prostate Cancer) trial was designed to test the efficacy of olaparib in metastatic castration-resistant prostate cancer.

Of the 50 patients enrolled in the TOPARP-A study, 49 were evaluable for response—16 had prostate cancers with a deleterious aberration in homologous DNA repair genes, and 14 responded to treatment. Serial blood samples were drawn from 46 patients and results reported in Cancer Discovery.

Targeted and whole-genome sequencing of serial cfDNA was conducted. The authors found that a decrease in the cfDNA concentration independently associated with outcome in multivariable analyses (hazard ratio [HR] for overall survival at week 8, 0.19; 95% CI, 0.06 to 0.56; P = .003). Somatic mutations documented in the tumor tissue were also detected in the cfDNA. Importantly, the allele frequency of somatic mutations decreased in responding patients (χ² P<.001).

The authors also identified a mechanism of resistance to olaparib in the form of multiple subclonal aberrations that reverted germline and somatic DNA repair mutations in BRAC2 and PALB2.

“These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer,” the authors concluded. cfDNA analyses, they wrote, can allow disease molecular stratification, response assessment, and facilitate the study of emerging resistance clones in the tumor.

Researchers at The Institute of Cancer Research who have been involved in developing this test for cfDNA believe that this test could, in the future allow the PARP inhibitor olaparib to become a standard treatment for advanced prostate cancer, by targeting the drug at the men most likely to benefit, picking up early signs that it might not be working, and monitoring for the later development of resistance.