DNA Repair Defects Are Strong Targets for Therapeutic Development in Prostate Cancer

Ariela Katz
Published: Monday, Jun 11, 2018
Maha H. Hussain, MB ChB

Maha H. Hussain, MB ChB

The use of poly (ADP-Ribose) polymerase (PARP) inhibitors in patients with a variety of tumor types is backed by a growing body of research. According to Maha Hussain, MD, the Genevieve Teuton Professor of Medicine and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois, there is now strong justification for clinical trials of PARP inhibitors in patients with prostate cancer.

“Metastatic prostate cancer is very complex, with a marked inter- and intra-patient heterogeneity and diversity. Therapy development, from my perspective, must focus on the totality of the biology if we want better care for our patients. DNA repair deficiencies have emerged as a promising therapeutic target in metastatic castration-resistant prostate cancer [mCRPC],” Hussain said during a presentation at New York GU™: 11th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies.

She noted that there are compelling data implicating PARP-1 in the mediation of DNA repair responses to alkylating agents, cellular survival in BRCA-deficient cells, and androgen receptor (AR)-mediated prostate cancer cellular proliferation. Further, PARP-1 interacts with the androgen signaling cascade, and castration-resistant tumor cells exhibit increased PARP-1 activity.

These data prompted a clinical trial looking at the combination of temozolomide (Temodar) and the PARP inhibitor veliparib (ABT-888) in patients with mCRPC, with the idea to replicate what was done preclinically. However, the overall results were not that promising, with a prostate-specific antigen (PSA) response rate of 8% based on 2 of 25 evaluable patients achieving a confirmed PSA decline of ≥30%. In the remaining 23 patients, 13 had stable PSA and 10 had PSA progression. None of the 16 patients with measurable disease for whom data were available achieved an objective response.1

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