This new agent, Olaparib (“Lynparza,” AstraZeneca), is the best developed drug in a new family of therapeutics termed PARP inhibitors. Olaparib is currently FDA approved for the treatment of advanced ovarian cancer where it has shown gratifying effectiveness. Oliparib was FDA approved in January 2016 for use in selected prostate cancer patients (see full note at article conclusion).
So … what is PARP, its biologic function, and what benefit accrues to selected prostate cancer patients from its inhibition?
In the normal state, the random mutations that occur frequently in the course of cellular proliferation can perturb the desired fidelity of passing along accurate copies of our DNA to the next generation of cells. These mutations can result in damaged DNA, i.e. resulting in “breaks” in proper sequences in the genetic code. The function of the PARP molecule is to repair those damaged regions.
However, successful cancer therapy with chemo- and radiation-therapy inflict their lethal damage by causing single- and double-strand DNA breaks, which, if unrepaired, lead to the desired outcome — cellular death. In these settings it is clearly undesirable to have these damaged sites repaired by a functioning PARP. Hence the role of PARP inhibition.
The two major families of DNA repair molecules are BRCA 1 & 2, and PARP. Both repair DNA damage. It is estimated that 6% of men are born with a dysfunctional mutation in BRCA 1 or 2. We now know that as prostate cancer progresses through sequences of treatments toward castration-resistant prostate cancer (CRPC) the number of men developing dysfunctional mutations in one of the BRCA set rises to an estimated 20 – 30%. In these men PARP shoulders the full responsibility of DNA repair. The role for Olaparib, the PARP inhibitor, is to insure that damaged DNA is not repaired by the remaining functional repair molecule, PARP, and that cell death follows.
At this time, the identification of mutations in the BRCA genes by genetic analysis provides the best predictor of which men will benefit from Olaparib.
Discussion of the current NEJM study:
With that background in mind, we can turn to a summary of the New England Journal of Medicine article by Mateo, De Bono et al., October 29, 2015: “DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.” This study clearly identifies Olaparib as an important forthcoming drug for this disease and is a notable early entry in the effort to molecularly stratify prostate cancer as to sensitivity to specific drugs. The report focuses on 49 well-studied men whose mutation profiles were analyzed, preferable on fresh biopsy tissue from metastatic sites or from archival formalin-fixed tissue from earlier sampling. Eighty percent of the men had metastatic prostate cancer which had progressed through four or more prior treatments – prostatectomy, hormone suppression (including Zytiga and Xtandi), radiation and chemotherapy.
A unique feature of the work-up was enumerating the number of circulating tumor cells (CTC) using the commercially available CellSearch system. Imaging studies recorded the size and location of metastases. The median values for age was 67; PSA, 349.5 ng/mL; and CTCs, 37 per 7.5 ml blood (<5 are considered “insignificant”). Olaparib was administered by mouth at 400 mg twice daily.
Response to Olaparib was determined by standard criteria for evaluating objective decrease in lesion size. A response required a > 50% decline in PSA and reduction in CTC to <5 CTCs/7.5 ml blood. Median follow-up was 14.4 months.
Of the 49, 16 men had mutations, either present at birth (determined on saliva) or acquired (determined on biopsy tissues or blood). These mutations were found in at least one of four genes: BRCA2, ATM, CHEK, and Fanconi Anemia gene, all of which have DNA repair function.
Of the 16 men exhibiting mutations in at least one of the four DNA repair genes, 15 (88%) met the response criteria, indicting that the identification of only one of those genes was 94% specific for response. All of the 7 men with BRCA2 responded; 4/5 with ATM mutations also responded.
Overall survival in the marker-positive group was 13.8 months v 7.5 in the marker-negative men. Twelve men were on treatment for more than 6 months, and 4 for more than one year.
Of the 16 men with elevated CTC counts, 15 dropped below 5 CTCs during treatment.
Based on the entire study cohort of 49 men, the median overall survival was 10.1 months with 33% responding.
Announcement of FDA approval (From UROToday, January 28, 2016):
“AstraZeneca announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for the oral poly ADP-ribose polymerase (PARP) inhibitor Lynparza (olaparib) for the monotherapy treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer (CRPC) in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent (abiraterone [Zytiga] or enzalutamide [Xtandi].”
Cancer treatment is entering the new period of individualized medicine. This study of Olaparib is an excellent example of its application in prostate cancer and underscores the benefit of genomic analysis of a man’s cancer. For those men with selected mutations this drug will likely become an important addition to treatment, either as monotherapy on in combination. The prevalence of mutations in the BRCA gene increases to about 20 – 30% during the course of treatment placing a significant number of men in line for benefit from Olaparib.