Immunotherapy: A Glimmer of Hope for Metastatic Prostate Cancer

Vishal Jindal

Disclosures

Chin Clin Oncol. 2018;7(6) 

In This Article

Parp Inhibition in Prostate Cancer

PARP [poly (ADP Ribose) polymerase] is an enzyme which initiate single stranded DNA repair. In patient with underlying DNA repair problem, if we inhibit PARP there will be no DNA repair and cell will die. This is the basic principle of action of PARP inhibitors. One study showed that genomic testing from bone and soft tissue metastasis of CRPC has DNA repair alterations. There are aberrations in androgen receptor (AR), TP53, PTEN, BRCA1/2 and ATM genes. It also showed that 89% of these are clinically actionable DNA mutation and frequency of these aberrations increase with progression of disease.[48] Olaparib is an oral PARP inhibition, which is approved for BRCA1/2 mutant ovarian cancer.[49] As prostate cancer patients also have this mutation, active PARP inhibition can be a promising treatment. In a phase 2 study where mCRPC patients not responding to standard therapy are treated with Olaparib and mutational status was assessed by genomic sequencing. It showed that 33% patients have high response to Olaparib therapy and it was associated with defect in DNA repair gene. BRCA and ATM mutations were found in 10% and 12% of patients respectively, out of 49 patients. All patients with BRCA mutations and 80% of ATM mutations had clinical response to Olaparib. It was a small study but it prompted a new therapy for CRPC.[50]

PARP inhibition leading to absence of DNA repair and cell death, will increase the antigenicity as there will be increased cytosolic double stranded DNA.[51] And this enhanced antigenicity will may increase the efficacy of immune check point inhibitors. Therefore, studies are going on regarding combination therapy of olaparib with durvalumab (PD-L1 inhibitor) in prostate cancer (NCT02484404). At 2017 Annual meeting of American Society of Clinical Oncology, preliminary results were presented, which showed >50 reduction in PSA in 43% patients who got treatment for 2 months.[52] Further studies are going on regarding individual and combination therapies of Olaparib, which have been summarized in Table 5. Two new PARP inhibitors Rucaparib (NCT02975934) and Niraparib (NCT02854436) are also under studies for therapy for CRPC.

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