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DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer
Joaquin Mateo1, Suzanne Carreira, Shahneen Sandhu
1From the Institute of Cancer Research (J.M., S.C., S.S., S.M., H.M., R.P.-L., D.N.R., A.O., N.T., G.B., N.P., P.F., A.G., I.F., C.P., G.S., D.B., J.G., Z.Z., C.T.W., R.F., R.R., B.E., G.F., D. Roda, W.Y., R.B., H.P., R.A., A.S., R.E., G.A., C.J.L., A.A., E.H., J.S.B.), the Royal Marsden NHS Foundation Trust (J.M., S.S., R.P.-L., A.O., N.T., D.B., Z.Z., R.F., D. Roda, R.E., G.A., J.S.B.), and University College London Hospital (U.M.), London, Queen's University, Belfast (S.J.), University of Leeds, Leeds (C.R.), Churchill Hospital, Oxford (A.P.), University of Liverpool, Liverpool (S.H.), Beatson West of Scotland Cancer Centre, Glasgow (R.J.), and Christie Hospital, Manchester (T.E.) - all in the United Kingdom; the University of Michigan, Ann Arbor (D. Robinson, Y.-M.W., X.C., L.P.K., F.Y.F., A.M.C.); Weill Cornell Medical College, New York (M.A.R.); and Thomas Jefferson University, Philadelphia (K.E.K.).
Background:
Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.
Methods:
We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.
Results:
Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.
Conclusions:
Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
Insights
Metastatic castration-resistant prostate cancer patients with DNA-repair defects responded well to the PARP inhibitor olaparib. This targeted therapy shows promise for patients with specific genetic mutations, offering a new treatment avenue.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Prostate cancer treatment lacks molecular stratification.
- Metastatic castration-resistant prostate cancer (mCRPC) is challenging to treat.
- DNA-repair defects are present in some mCRPC tumors.
Purpose of the Study:
- To evaluate the efficacy of poly(ADP-ribose) polymerase (PARP) inhibition with olaparib in mCRPC patients with DNA-repair defects.
- To identify predictive biomarkers for response to olaparib in mCRPC.
Main Methods:
- Phase 2 clinical trial of olaparib (400 mg twice daily).
- Primary endpoint: response rate (objective response or PSA/circulating tumor cell reduction).
- Tumor biopsies analyzed using next-generation sequencing, exome/transcriptome analysis, and digital PCR for DNA-repair gene alterations.
Main Results:
- 16 of 49 evaluable patients (33%) responded to olaparib.
- DNA-repair gene defects (BRCA1/2, ATM, etc.) identified in 33% of evaluable patients.
- 14 of 16 patients (88%) with DNA-repair defects responded to olaparib, including all 7 with BRCA2 loss.
Conclusions:
- Olaparib demonstrates high response rates in mCRPC patients with DNA-repair gene defects.
- Targeted PARP inhibition is a viable treatment strategy for this molecularly defined subgroup.
- Biomarker-driven therapy can improve outcomes in advanced prostate cancer.
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