Targeting defective DNA repair in prostate cancer.
Antineoplastic Agents, Immunological
/ therapeutic use
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
DNA Repair
Humans
Male
Molecular Targeted Therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ therapeutic use
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Randomized Controlled Trials as Topic
Journal
Current opinion in oncology
ISSN: 1531-703X
Titre abrégé: Curr Opin Oncol
Pays: United States
ID NLM: 9007265
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
pubmed:
18
7
2020
medline:
23
12
2020
entrez:
18
7
2020
Statut:
ppublish
Résumé
Prostate cancer is the second leading cause of cancer death in men. Characterization of the genomic landscape of prostate cancer has demonstrated frequent aberrations in DNA repair pathways, identifiable in up to 25% patients with metastatic disease, which may sensitize to novel therapies, including PARP inhibitors and immunotherapy. Here, we summarize the current clinical landscape and future horizons for targeting defective DNA repair pathways in PC. Several clinical trials have demonstrated efficacy of different PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), most pronounced in those with BRCA mutations. The PROfound trial is the first positive phase 3 biomarker-selected trial to demonstrate improved outcomes with a targeted treatment, Olaparib, in mCRPC. Whilst the Keynote-199 trial failed to demonstrate efficacy of immune-checkpoint inhibitor pembrolizumab in unselected mCRPC patients, there was evidence of response in those harbouring DNA repair defects. These landmark trials represent a significant advance towards personalization of PC therapy. However, resistance remains inevitable and there is a lack of reliable predictive biomarkers to select patients for treatment. Characterization of resistance mechanisms, and validation of novel biomarkers is critical to maximize clinical benefit and inform novel treatment combinations to improve outcomes.
Identifiants
pubmed: 32675592
doi: 10.1097/CCO.0000000000000654
pii: 00001622-202009000-00015
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
503-509Références
Rawla P. Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Epidemiology of Prostate Cancer. World J Oncol 2019; 10:63–89.
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. J Am Med Assoc 1999; 281:1591–1597.
Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet 2018; 50:645–651.
Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016; 375:443–453.
Goodall J, Mateo J, Yuan W, et al. TOPARP-A investigators. Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov 2017; 7:1006–1017.
Nicolosi PLW, Michalski ST, Freschi B, et al. Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer. J Clin Oncol 2017; 35: (15_Suppl): 5009–15009.
Isaacsson Velho P, Silberstein JL, Markowski MC, et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate 2018; 78:401–407.
Antonarakis ES, Shaukat F, Isaacsson Velho P, et al. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol 2019; 75:378–382.
Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol 2019; 5:471–478.
Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what's next after PARP inhibitors? Nat Rev Clin Oncol 2018; 15:564–576.
Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373:1697–1708.
Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2020; 21:162–174.
Sandhu SK, Hussain M, Mateo J, et al. LBA8 PROfound: phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Ann Oncol 2019; 30: (Suppl 9): IX188–IX189.
Abida W, Campbell D, Patnaik A, et al. Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): updated analyses. Hematology/Oncology 2019.
Smith MR, Sandhu SK, Kelly WK, et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD. J Clin Oncol 2019; 37: (7_Suppl): 202–1202.
De Bono JS, Higano CS, Saad F, et al. TALAPRO-1: an open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT). J Clin Oncol 2019; 37: (7_Suppl): TS342–TS1342.
de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020; 382:2091–2102.
Smith MR, Sandhu SK, Kelly WK, et al. Niraparib Shrinks BRCA-Mutated Prostate Tumors. Cancer Discov 2019; 9:OF7doi:10.1158/2159-8290.CD-NB2019-030.
doi: 10.1158/2159-8290.CD-NB2019-030
De Bono JS, Mehra N, Higano CS, et al. TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA). J Clin Oncol 2020; 38: (6_suppl): 119.
LynparzaTM (olaparib) granted Breakthrough Therapy designation by US FDA for treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer. Available at: https://www.astrazeneca.com/media-centre/press-releases/2016/Lynparza-Olaparib-granted-Breakthrough-Therapy-Designation-by-US-FDA-for-treatment-of-BRCA1-2-or-ATM-gene-mutated-metastatic-Castration-Resistant-Prostate-Cancer-28012016.html. [Accessed 24 April 2020]
Clovis Oncology, Inc. - Clovis Oncology Receives Breakthrough Therapy Designation for Rubraca1 (rucaparib) for Treatment of BRCA1/2-Mutated Metastatic Castration Resistant Prostate Cancer (mCRPC) . Available at: https://ir.clovisoncology.com/investors-and-news/newsreleases/press-release-details/2018/Clovis-Oncology-Receives-Breakthrough-Therapy-Designation-for-Rubraca-rucaparib-for-Treatment-of-BRCA12-Mutated-Metastatic-Castration-Resistant-Prostate-CancermCRPC/default.aspx. [Accessed 24 April 2020]
Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Niraparib for the Treatment of Metastatic Castration-Resistant Prostate Cancer. Available at: https://www.janssen.-com/us/sites/www_janssen_com_usa/files/janssen_announces_us_fda_breakthrough_therapy_designation_granted_for_niraparib.pdf. [Accessed 24 April 2020]
Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013; 19:1381–1388.
Quigley D, Alumkal JJ, Wyatt AW, et al. Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov 2017; 7:999–1005.
Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 Study. J Clin Oncol 2019; 38:395–405.
Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161:1215–1228.
Rodrigues DN, Rescigno P, Liu D, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 2018; 128:4441–4453.
Shenderov E, Isaacsson Velho P, Awan AH, et al. Genomic and clinical characterization of pulmonary-only metastatic prostate cancer: a unique molecular subtype. Prostate 2019; 79:1572–1579.
Pritchard CC, Morrissey C, Kumar A, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun 2014; 5:4988.
Schweizer MT, Antonarakis ES, Bismar TA, et al. Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. JCO Precis Oncol 2019; 3:10.
Criscuolo D, Morra F, Giannella R, et al. Identification of novel biomarkers of homologous recombination defect in DNA repair to predict sensitivity of prostate cancer cells to PARP-inhibitors, 2019. Int J Mol Sci 2019; 20:3100.
Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 2017; 355:1152–1158.
Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases, 2013. Cold Spring Harb Perspect Biol 2013; 5:a012716.
Mateo J, Lord CJ, Serra V, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol 2019; 30:1437–1447.
Yap TA, Plummer R, Azad NS, Helleday T. The DNA damaging revolution: PARP inhibitors and beyond. Am Soc Clin Oncol Educ Book 2019; 39:185–195.
Christenson ES, Antonarakis ES. PARP inhibitors for homologous recombination-deficient prostate cancer. Expert Opin Emerg Drugs 2018; 23:123–133.