I would like to thank Dr. Bruce Montgomery, University of Washington and Seattle Veterans’ System, and Dr. Song Zhao, Cancer Institute, Swedish Medical Center, Seattle, for their valuable input into this article and especially in the sections regarding their protocols.
A new category of drugs is under development that will undoubtedly shortly assume its place among the several new agents that are already prolonging the lives of men with prostate cancer.
The message is becoming clear: If a man is born with mutations in a specific cluster of genes that are defective in repairing damaged DNA, or acquires them during the course of treatment, he may be a candidate for an emerging therapy, i.e. PARP inhibition. Early studies have shown promise in men even after standard regimens have failed. At this point, these drugs that inhibit PARP have been researched in men with metastatic castration-resistant prostates cancer. Currently, they are available only on protocol.
What is PARP and what is its function?
During life, an unimaginably enormous number of cell divisions occur each day, divisions which in many cases fail to replicate DNA with the requisite fidelity. Those errors, if uncorrected, can lead to the development and the acceleration of cancer. The first line of defense in repairing these DNA defects is carried out mainly by the genes, BRCA1 and 2, ATM, along with a supporting team of genes — CHEK 2, PALB2, FANCA, and RAD51. When one or several of these genes are dysfunctional and the defect remains uncorrected, the default repair mechanism is PARP1, the most prominent member of the PARP family, accompanied by a team of associated molecules. PARP is the acronym for the enzyme “poly (ADP) ribose polymerase.” PARP inhibitors deactivate this second line of defense with the consequence of cell death. The DNA damage of concern results not only from naturally occurring random faulty gene transcription but also from radiation and chemotherapy, which can overwhelm DNA repair in a cell in which it is already compromised. The biological terms for this type damage are “single and double strand breaks” in DNA.
What drugs inhibit PARP repair function?
A new family of drugs has been developed to incapacitate PARP-based repair, each drug being slightly different. The names of the major drugs currently under protocol testing are olaparib, velaparib, rucaparib, talazoparib, and niraparib.
Establishing the frequency of genes disrupting the DNA repair process found in men with metastatic cancer:
A groundbreaking study addressing this issue is: “Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer,” NEJM Aug 4, 2016, the product of an international consortium with Dr. Peter Nelson (Fred Hutchinson Cancer Research Center, Seattle) as the senior author. They analyzed 692 men with metastatic prostate cancer and identified 82 men with mutant genes that disable the DNA repair process: notably in BRCA2, 5.3%; ATM, 1.6%, CHEK2 1.9 %, and PALB2, 4%. All together these adverse genes occurred in 11.8% of these men with metastatic disease. This significant percentage should be compared to the 4.6% prevalence in men with localized cancer and the 2.7% found in men not known to have cancer, based on data from 53,105 men sequenced in the Exome Aggregation Consortium.
These germline (i.e. inherited) mutations were identified in specimens of saliva, buccal smears, whole blood, or from non-cancerous tissue. In addition, tumor DNA was obtained from 91 patients at the University of Washington, and 43 patients at the University of Michigan through their rapid autopsy programs.
The clinical importance of this study is to alert both clinicians and patients that a significant percentage of men, even after failing prior therapies, may be candidates for protocols testing PARP inhibition, but also for platinum chemotherapy.
Early indication of effectiveness of PARP inhibition with olaparib:
The NEJM in October 2015 published the report by Mateo et al. “DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer,” which reported that olaparib (400 mg orally twice daily) led to an 88% response in 14 of 49 heavily pretreated patients “including all 7 patients with BRCA2 loss … and 4 of 5 with ATM aberrations.” Response was defined as a >50% PSA decline, a decrease in circulating tumor cells, or objective radiographic improvement. The median overall survival in the biomarker positive group was 9.8 months vs 2.7 months for those men not carrying these mutations. This study led to the FDA putting olaparib on a fast track for study in those men with germline or acquired mutations in BRCA1, BRCA2, and ATM.
Current status of PARP inhibition in prostate cancer:
An excellent and comprehensive review, “Treatment strategies for DNA repair-deficient-prostate cancer,” by Teply and Antonarakis (Expert Review of Clinical Pharmacology, June 2017) begins with the perspective:
- “Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts and the prevalence of mutations in DNA repair pathway gene in patients with advanced and metastatic disease approaches 20-25%.”
The mutational landscape of prostate cancer is extensive, but this study focused on clinically “actionable” mutations, that is, mutations that can be targeted by drug intervention. The prime “actionable” targets are the mutations in the DNA-repair gene — mutations that the Nelson study found enriched in advanced and metastatic disease, as opposed to fewer in primary prostate cancer.
Antonarakis refers to a major research article (Robinson et al., Cell, 2015 May) that reported on biopsies on 150 men with metastatic CRPC: “Aberrations in BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancer,” … of which “89% of affected individuals harbored a clinically actionable aberration … ,” (quote from Robinson).
The clinical utility of carrying one of these mutations in DNA-repair genes is at least threefold because of conferring increased sensitivity to:
- regimens employing PARP inhibition;
- platinum chemotherapy (usually combined with another agent);
- Bipolar Androgen Therapy (BAT)
- immunotherapy regimens using checkpoint inhibitors.
How can a man’s mutational status be determined?
NCCN recommendations: “ … due to the high prevalence of germline mutations, the panel recommends consideration of germline testing for all men with metastatic and high-/very-high-risk clinically localized prostate cancer.”
The most straightforward way is to submit a sample of normal blood or a cheek swab for testing for inherited mutations. There are many assays which can be used but insurance coverage for this testing varies. One option is testing of saliva through Color Genomics (color.com) and requesting the Hereditary Cancer Test Kit ($249). This test analyzes and reports on 30 genes — including the genes relevant for DNA-repair defects: BRCA 1 & 2, ATM, CHEK2, PALB2, RAD51C&D. Having one of these mutations qualifies a man as eligible (if he meets other requirements) for protocols testing PARP inhibitors. As noted above, the Nelson article found that 11.8% of men with metastatic prostate cancer carry one or more of the mutations.
Men with advanced disease and those with mCRPC having progressed on prior treatments will likely have acquired additional mutations (“somatic’) adding up the total estimate of 20-25% estimated by Atonarackis. “About half of these patients with somatic DNA repair aberrations also have germline defects in these same DNA repair genes, 8- 12% of the total,” (Terada, Atonarackis et al., Therapeutic Advances in Medical Oncology June 2017) .The real-time mutational load can be assessed (and re-assessed) in a blood sample using the remarkable technique of analyzing circulating-free DNA. Although potentially very useful, all of the commercial assays are dependent on the amount of DNA present in the blood. Dr. Antonarackis commented “The currently available cfDNA platforms are: Guardant360, FoundationACT, PGDx PlasmaSELECT.”
Currently recruiting protocols across the USA:
As of the date of this Commentary there are 6 open and recruiting protocols using PARP inhibitors (with a variety of formulations and different drug combinations). But this is a very actively evolving field and more studies will likely be added. For those men not in the Seattle area, clinicians and patients should check clinicaltrials.gov to see what is available in their region.
Protocol available through Swedish Medical Center, Seattle.
For men in the Seattle area a Phase 2 protocol is open and recruiting through the Swedish Medical Center (NCT03148795): “A study of Talazoparib in Men with DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer. Men are eligible who have previously received taxane-based chemotherapy (docetaxel and/or cabazitaxel) and progressed on either enzalutamide [Xtandi] and/or aberaterone [Zytiga].” DNA damage repair deficiency will be assessed centrally using a panel of genes likely to sensitize to PARP inhibition l. Circulating tumor cells will be monitored for response along with the standard outcome metrics.
Talazoparib (Pfizer) showed promising responses (42% and 50%, respectively) and a tolerable safety profile in a study of patients with BRCA mutation-associated breast and ovarian cancer. Fatigue, anemia and reduced platelet counts were seen in 37%, 35%, and 18%, respectively. (de Bono et al., CANCER DISCOVERY, June 2017)
The principal investigator of this trial at Swedish Medical Center is Dr. Song Zhao (Contact – Research coordinator, Erik Bailey, 206-215-2397). There are many additional particulars about protocol eligibility that should be discussed with Dr. Zhao or the research coordinator.
Protocols available through the Veteran’s Administration Hospital System, Seattle.
Two protocols using PARP inhibitor rucaparib are available through the Veterans’ Administration for veterans with prostate cancer who have DNA repair defects. One study, TRITON2 (NCT02952534) is open to men with mCRPC who previously received taxane-based chemotherapy and also progressed on either Xtandi or Zytiga. The second study, TRITON3, compares rucaparib to the physicians’ choice of therapy. Rucaparib will be available to those men who had progressed on the alternative regimen.
Dr. Bruce Montgomery is the principal investigator. Contact research coordinator Akemi Minamoto (206-277-5598) for further discussion of details.
BOTTOM LINE:
Identification of patients with defects in DNA repair genes and their treatment with PARP inhibition is a significant step toward precision medicine. This emerging therapy will only become more effective as further research defines the proper selection of patients and the timing of PARP inhibitors in the sequence of therapy. Considering that, as currently estimated, 20 – 25% of men could benefit from this treatment. Therefore, awareness of mutations in DNA repair genes is especially clinically relevant.