Gene-targeted and personalized therapy currently exists for a small handful of diseases, but that list may soon include prostate cancer.
Prostate cancer represents a huge health risk for half the world’s population, as it is the most common form of cancer in men. Current treatments for the disease are confined to the affected prostate tissue, commonly involving radiation and chemotherapy aimed at the cancer cells in the prostate, or surgical removal of the prostate itself. But the line of defense against prostate cancer may have strengthened dramatically with olaparib, a drug that specifically targets DNA-repair genes.
Olaparib is not a novel drug. Manufactured by Astrazeneca under the tradename Lynparza, olaparib was recently approved by the FDA as a cancer drug for ovarian cancers associated with BRCA1/2 mutations. In these types of cancers, there’s a propensity of the cancer cells to rely only on the enzyme poly ADP-ribose polymerase (PARP) to repair its constantly dividing DNA. The drug olaparib exploits this vulnerability and acts as a PARP inhibitor, effectively killing the cancer cells by allowing DNA damages to go unrepaired, while having no adverse effects on normal cells.
BRCA1/2 mutations are also the cause of some prostate cancers. In a recent study by the Institute of Cancer Research in London, olaparib was given to a cohort of 49 men with treatment-resistant and metastatic prostate cancer. Within this cohort, 16 men showed tumor mutations in DNA damage-repair genes, including BRCA1/2, ATM, PALB2, CHEK2, FANCA, and HDAC2. The team reported significantly higher response rate to olaparib for these 16 men out of the group of 49, citing greater than 50% reduction in prostate specific antigen (PSA) levels, decreased prostate cancer cells, and shrinkage of secondary tumors.
"This trial is exciting because it could offer a new way to treat prostate cancer by targeting genetic mistakes in cancers that have spread," said Dr Áine McCarthy of the UK Cancer Research.
Beyond the immediate positive response of the trial, the real excitement for the research team rests in the identification of the mutations in DNA-repair genes from the 16 men with the best response to olaparib. Notably these genes have all shown lethal adverse interactions with PARP inhibitors, representing a promising avenue for precision medicine in the treatment of prostate cancer.
Though hopeful of combining genetic analysis and targeted drug therapy for prostate cancers, Dr. Emma Hall, study co-leader of the ICR, stressed follow-up trials. With the results of this clinical study, the next steps will be to demonstrate the specificity and efficacy of olaparib on the subset of prostate cancers caused by DNA-repair mutations.
“The next trial includes only men with these mutations in their tumors, with the aim of proving that olaparib is highly effective for them," said Dr. Emma Hall.
Knowing the genetic mutations associated with each prostate cancer could redefine the clinical diagnosis and subsequent therapy for each patient. Those who exhibit tumor mutations in the DNA repair genes could be treated with PARP inhibitors as a first line of defense. Because the treatment is tailored to the patient’s genetic profile, the hope is that many more lives will be saved in the future.
Through active surveillance and screening, the mortality rate for prostate cancer has dramatically been reduced. However, prostate cancer remains one of the top leading causes of cancer-related deaths for men worldwide. The current study represents a huge achievement for prostate cancer treatment, identifying olaparib as a highly targeted prostate cancer drug. The study has also added to the groundwork for future clinical therapy that’s based on individual genetic profiles.
Watch the video to learn more about how PARP inhibitors like olaparib work!
Source: NEJM
