Phase II Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
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Purpose
Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical benefit for patients with solid tumors bearing germline or somatic alterations in DNA damage response (DDR) genes. Somatic alterations in DDR genes are common in advanced urothelial cancer, raising the possibility that PARP inhibition may confer therapeutic benefit in a molecularly selected subgroup of patients with metastatic urothelial cancer (mUC).
Methods
This single-arm, open-label, multi-institutional, investigator-initiated phase II study evaluated the antitumor activity of olaparib 300 mg twice a day in participants with mUC harboring somatic DDR alterations. Patients had progressed despite previous platinum-based chemotherapy, or were cisplatin-ineligible, and harbored somatic alterations in at least one of a prespecified list of DDR genes. The primary end point was objective response rate; secondary end points were safety, progression-free survival (PFS), and overall survival (OS).
Results
Overall, 19 patients with mUC were enrolled and received olaparib; the trial closed early before slow accrual. The median age was 66 years (range 45-82). Nine patients (47.4%) had received previous cisplatin chemotherapy. Ten patients (52.6%) had alterations in homologous recombination (HR) genes: eight patients (42.1%) had pathogenic BRCA2 mutations and two patients carried alterations in other HR genes. No patients achieved a partial response although six patients achieved stable disease lasting 2.13-16.1 months (median 7.69). The median PFS was 1.9 months (range 0.8-16.1), and the median OS was 9.5 months (range 1.5-22.1).
Conclusion
Single-agent olaparib showed limited antitumor activity in patients with mUC and DDR alterations, which may be related to poorly characterized functional implications of particular DDR alterations and/or cross-resistance with platinum-based chemotherapy in a disease where such therapy represents standard first-line treatment.
Read an interview about the study here and expert commentary about it here.
Read the full article
Phase II Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
Primary Source
JCO Precision Oncology
Source Reference: