by C.H. Weaver M.D. updated 1/2021
Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine requires molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome to identify specific genetic abnormalities that can be targeted for treatment. Once a genetic abnormality is identified, a specific targeted therapy that attacks a specific mutation or other prostate cancer-related change in the DNA programming of the cancer cells can be selected for treatment. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy.” Patients should make sure NGS testing is performed on both their tissue and blood at the time of diagnosis if possible.
Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes. So far, targeted therapies for prostate cancer have focused mainly on blocking androgen receptors or reducing hormone production. Eventually, prostate cancers ultimately however develop resistance to ADT leading to cancer progression. As with other types of cancer identifying the genetic drivers of prostate cancer is necessary to further improve treatment.
The first precision cancer medicine has been identified for the treatment of prostate cancer and researchers have begun to identify additional genetic biomarkers that can be targeted with precision cancer medicines and immunotherapy. In an analyses of 3,476 prostate cancer samples doctors found that 57% had genomic alterations under investigation as biomarkers for precision cancer medicines.
Cancer Driving Mutations Identified in Prostate Cancer
- BRCA 2 ~ 10%
- PTEN 30%- AKT inhibitors may be effective
- Microsatellite instability – high (MSI-H)
- PIK3CA ~ 6%
- CDK12 ~ 5%
- TP53 ~ 53%
- TMPRSS2ERG ~ 31
- AR ~ 22%
- MYC ~ 12%
- RB1 ~ 9%
- APC ~ 9%
PARP Inhibitors for BRCA Mutations
The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy are called PARP inhibitors.
BRCA1 and BRCA2 are critical DNA damage repair (DDR) genes that act to mend any damaged DNA and are present in ~ 5-10% of prostate cancer patients. Mutations in BRCA genes render cells highly susceptible to acquiring other mutations and developing into cancer. However, in order to survive, cancer cells that have lost BRCA1, BRCA2 or many other DNA repair genes become dependent on the function of PARP to maintain sufficient integrity of their DNA. Thus, cancer cells with mutations in BRCA1/2 are highly sensitive to PARP-inhibiting drugs leading to cell death and possibly a slow-down or stoppage of tumor growth. (1,2)
About Lynparza (olaparib)
The PARP-inhibitor Lynparza (olaparib) was evaluated in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations in DNA damage repair (DDR) genes. (2)
In this trial Lynpara was directly compared to treatment with a physician’s choice of either Zytiga (abiraterone) + prednisone or Xtandi (enzalutamide) in men with mCRPC who had failed previous treatment and who were found to have a mutation in a DDR gene. The trial grouped patients with BRCA1, BRCA2, or ATM mutations together, and those with mutations in any of 12 other predetermined DDR genes.
The study authors reported that 22% of men treated with Lynpara responded to treatment compared to only 4.5% of Xtandi or Zytiga treated patients. Overall 33% of men with BRCA1, BRCA2, or ATM mutations responded to Lynpara treatment compared to only 2.3% of Xtandi or Zytiga treated patients. This translated into improving overall survival by an average of 3.39 months (18.5 vs 15.11 months). Lynparza also delayed the time to cancer progression. (8)
The mismatch repair system (MMR) is a single-strand DNA repair mechanism that recognizes and reverses DNA base mismatches, insertions, and deletions. Defective MMR results in microsatellite instability (MSI), a condition of hypermutability of short repetitive sequences in the genome that is associated with resistance to chemotherapy but sensitivity to immunotherapy. (3) Results indicate that favorable responses to PD-1/PD-L1 therapy may occur in about 50 percent of patients with tumors that have a defective mismatch repair (dMMR) status and a MSI-H score. (3-7)
- Chung JH, et al. JCO Precis Oncol.2019;doi:10.1200/PO.18.00283.
- Hussain M, et al. Abstract LBA12_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
- Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. [Lancet Oncol](https://www.thelancet.com/article/S1470-2045(14%2970189-5/abstract). 2014;15(7):700–712.
- Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):40–47.
- Le DT, Uram JN, Bartlett BR, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520
- Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.
- Nava Rodrigues D, Rescigno P, Liu D, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018;128(10):4441–4453.
- N Engl J Med 2020; 383:2345-2357