Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

Abstract

A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness.

Interaction mechanism of olaparib binding to human serum albumin investigated with NMR relaxation data and computational methods

“…2(D) shows the calculated 1/DR SE lN of H8 against varying concentrations of OLA at different temperatures. According to eqn (12) and (13), the K values were found to be 591.1 AE 29.8 mol À1 L at 298 K, 362.8 AE 29.9 mol À1 L at 304 K, and 314.2 AE 30.1 mol À1 L at 310 K. Therefore, the OLA-HSA system was more stable at 298 K than at the two other temperature settings, and this observation was consistent with the decrease in the affinity index of H8 proton with HSA as temperature increased.…”

“…8,9 Olaparib (OLA), a potent oral poly(ADP-ribose) polymerase (PARP) enzyme inhibitor, which plays essential roles in controlling DNA repair and eventually killing cancer cells, can be used as a targeted therapy for certain types of cancer, such as breast and ovarian cancer, in people with hereditary BRCA mutations. [10][11][12] Ovarian cancer is the seventh-most common malignant tumor among gynecologic systems. 13 To treat BRCAmutated ovarian cancer and to overcome frequent recurrence and chemotherapeutic resistance of ovarian cancer, medical scholars prefer OLA as a PARP inhibitor because it has achieved satisfactory therapeutic outcomes.…”

Targeting genotoxic and proteotoxic stress‐response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

“…These approaches, while technically challenging, have a potential for clinical implementation as predictive biomarkers for treatment with PARPi, complementary to genetic analyses of BRCA1/2 , ATM or TMPRSS2‐ERG . Olaparib has also been recently reported to be effective in combination with, and as maintenance therapy after, first‐line endocrine therapy of prostate cancer …”

“…4,6,42 Olaparib has also been recently reported to be effective in combination with, and as maintenance therapy after, first-line endocrine therapy of prostate cancer. 44 Different therapeutic approaches will be required for castrationresistant PCa cases that are HR repair proficient. Based on our current data, we propose another treatment strategy, involving HDAC inhibitors such as vorinostat.…”

Familial/inherited cancer syndrome: a focus on the highly consanguineous Arab population

“…This highlights the impact of genetic testing in therapeutic strategies. [133][134][135][136] It should be noted that, genetic profiling has not replaced PSA monitoring, prostate gland MRIs, or biopsies for screening. The presence of mutations associated with prostate cancer encourages patients to undergo earlier and more frequent screening with the hope of earlier diagnosis and treatment.…”