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

• Published in: Molecular oncology Vol. 12; no. 4; pp. 561 - 576
• Main Authors: Feiersinger, Gertrud E., Trattnig, Kristina, Leitner, Peter D., Guggenberger, Fabian, Oberhuber, Alexander, Peer, Sarah, Hermann, Martin, Skvortsova, Ira, Vrbkova, Jana, Bouchal, Jan, Culig, Zoran, Santer, Frédéric R.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.04.2018; John Wiley and Sons Inc; Wiley
• Subjects: Analysis; Androgens; Androgens - metabolism; Antimitotic agents; Antineoplastic agents; Apoptosis; Cancer; Cancer therapies; Care and treatment; Castration; Cell culture; Cell cycle; Cell fusion; Cell Line, Tumor; Chemotherapy; combination therapy; Cytotoxicity; Deoxyribonucleic acid; DNA; Drug therapy; Endocrine therapy; Experiments; Health aspects; Humans; Lethality; Maintenance Chemotherapy - methods; maintenance therapy; Male; Medical research; Medicine, Experimental; Metastases; Metastasis; Mimicry; Models, Biological; Mutation; olaparib; PARP inhibition; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Prostatic Neoplasms, Castration-Resistant - therapy; Austria; Germany; United States > US; combination therapy; maintenance therapy; prostate cancer; PARP inhibition; olaparib; endocrine therapy
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12185

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. Prostate cancer first‐line endocrine therapies are effective in combination with olaparib in cells with BRCAness status. TMPRSS2:ERG is not a sensitizer for synthetic lethality with olaparib. Olaparib could be used as maintenance therapy sequenced to endocrine treatment.