A Novel Use of Olaparib for the Treatment of Metastatic Castration‐Recurrent Prostate Cancer

Abstract

Although mortality from prostate cancer has declined over the past 20 years as a result of early detection and treatment, the 5-year survival rate for men with prostate cancer who develop metastatic disease is only 29%. Current treatment options for metastatic castration-recurrent prostate cancer (mCRPC) are associated with toxicity and a limited durable response; therefore, additional lines of efficacious and minimally toxic therapy are needed. Olaparib, a poly(adenosine 5'-diphosphate) ribose polymerase (PARP) inhibitor, received a U.S. Food and Drug Administration breakthrough therapy designation in January 2016 for the treatment of patients with BRCA1/2 or ATM gene-mutated mCRPC based on results of a compelling phase II trial of olaparib in patients with advanced castration-resistant prostate cancer (TOPARP-A). This study found that men with mCRPC and genetic mutations in DNA damage repair genes had an overall response rate of nearly 90% with olaparib treatment. In this review, we describe current therapies for mCRPC, the rationale for anti-PARP therapies, the pharmacology of olaparib for prostate cancer, clinical trials of olaparib for mCRPC, our clinical experience with olaparib for prostate cancer at a comprehensive cancer center, and future directions of olaparib for the treatment of mCRPC. Olaparib may constitute a promising treatment to prolong survival in patients with mCRPC, with an acceptable adverse effect profile. As the role of PARP inhibition in prostate cancer and other malignancies becomes further elucidated, olaparib may be shown to be beneficial for other patient populations.

Recent Advances in Prostate Cancer Treatment and Drug Discovery

“…Other recent findings suggest that loss of the chromatin remodeler chromodomain-helicase-DNA-binding protein 1 (CHD1), which is often observed in advanced prostate cancer, increases the response to PARP inhibitors [ 79 , 80 ]. The encouraging clinical phase 2 results obtained with olaparib led to a breakthrough designation by the FDA and a phase 3 pivotal study is currently ongoing [ 81 ]. Conversely, the clinical results obtained for the PARP inhibitor veliparib given to mCRPC patients in addition to abiraterone acetate did not show a statistically significant improvement [ 82 ].…”

Olaparib: Transcending mutational barriers

“…This genetic instability of tumor cells with HRR mutations makes them vulnerable to cell death via PARP inhibitors. [1] Olaparib, a PARP inhibitor, received the United States Food and Drug Administration breakthrough therapy designation in January 2016[1] on the basis of the novel TOPARP-A trial,[2] for mCRPC patients with ATM or BRCA1/2 gene mutations who have received prior taxane-based chemotherapy or enzalutamide/abiraterone. Based on the preclinical studies suggesting synergistic activity[3] with androgen deprivation, a randomized, double-blinded, placebo-controlled Phase II trial comparing combination of olaparib with abiraterone in mCRPC irrespective of HRR gene mutations was recently published in the Lancet Oncology on June 4, 2018.…”

“…Although an important breakthrough, its applicability is limited only to patients with BRCA1/2 or ATM gene mutations. [1] Asim et al [3] in a genetic study demonstrated the concept of “synthetic lethality,” whereby androgen receptor inhibition leads to an increase in PARP activity, as occurs in cells with HRR mutations. Their study suggested the synergy between PARP inhibitors and drugs inhibiting androgen synthesis, forming the background for this study.…”

Emerging therapeutic agents for genitourinary cancers

“…This becomes a critical component for cancer cell survival [168]. PCs with DNA repair gene alterations have found to be sensitive to PARP inhibitors [169]. To this end, the PARP suppression in mCRPC first assessed in the TOPARP-A trial, which was significant for high response rates (88%) in patients with DNA repair gene deficits [170].…”