PARP Inhibition in Advanced Prostate Cancer

Summary and Comment |
October 28, 2015

PARP Inhibition in Advanced Prostate Cancer

  1. Robert Dreicer, MD, MS, FACP, FASCO

A third of patients with disease progression after chemotherapy responded to olaparib.

  1. Robert Dreicer, MD, MS, FACP, FASCO

Although much of the recent progress in managing metastatic castration-resistant prostate cancer (mCRPC) is based on targeting the androgen receptor, developments in understanding the molecular drivers of the disease are providing new avenues for drug development. For example, recent evidence suggests that in subsets of mCRPC patients, DNA-repair defects might be amenable to therapy with poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition.

To test this approach further, international investigators conducted a multicenter, single-group, open-label, phase II trial in which 50 mCRPC patients with evidence of disease progression after treatment with one or two chemotherapy regimens received the PARP inhibitor olaparib (400 mg twice daily) until disease progression or intolerable toxicity. All patients had received docetaxel; 98% had received abiraterone or enzalutamide; 58% had received cabazitaxel; and none had received cisplatin, cyclophosphamide, mitoxantrone, or a PARP inhibitor. Patients underwent biopsies at baseline and during therapy for whole-exome sequencing and transcriptome studies. The primary endpoint was response rate, defined as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response, prostate-specific antigen (PSA) response, or conversion of the baseline circulating tumor cell count.

One third of patients responded to olaparib. Median overall survival was 10.1 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes in a third of patients; most patients with these biomarkers responded to olaparib (88%), half of whom had BRCA2 loss. Anemia and fatigue were the major treatment-related adverse effects.

Comment

This important report offers prospective evidence that targeting specific molecular defects can potentially provide important clinical targets in mCRPC. Additional developments involving olaparib and other similar compounds will likely require trials using biomarker-selected patients to establish clinical benefit. The authors note the uneven data regarding the role of platinum agents in mCRPC and suggest that the DNA-repair defects may be associated with platinum sensitivity.

Editor Disclosures at Time of Publication

  • Disclosures for Robert Dreicer, MD, MS, FACP, FASCO at time of publication Consultant / Advisory board Medivation; Genetech/Roche; Bind Pharmaceuticals; Astellas Editorial boards Urology; Clinical Genitourinary Cancer; Current Urology Reports Leadership positions in professional societies National Cancer Institute (Co-Chair, GU Oncology Steering Committee); American Board of Internal Medicine (member, Medical Oncology Test Writing Committee); Bladder Cancer Advocacy Network (member, scientific advisory board)

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