PARP [poly (ADP-ribose) polymerase] is a nuclear RNA enzyme essential for repair of single strand DNA damage. It is the default program that repairs damaged DNA that remained unrepaired because of deleterious mutations in the BRCA family of genes, a cell’s first line of repair when DNA is damaged. The primary DNA repair genes, BRCA 1, 2 and ATM are termed ‘germline” i.e., inherited and present in all cells. When these DNA repairs genes are defective the cell relies upon the default PARP program to correct the DNA damage. The function of the currently FDA approved PARP inhibitors, olaparib (Lazaparib) and rucaparib (Rubraca) is to prevent PARP repair and cause cell death. Reviewed in detail in PCa Commentary Vol. 141
pca-commentary-141-parp-inhibition-therapy [control+click link] or visit website https://prostatecancerfree.org/prostate-cancer-news
Which Men Should Be Tested for Mutations in BRCA 1, 2 and ATM and Why: A Compressed summary.
Men with aggressive cancer at diagnosis are appropriate candidates for genomic testing i.e., men with Gleason 3 + 4, PSA values greater than 10 ng/mL and extracapsular extension, seminal vesicle involvement and greater 50% biopsy cores positive. These features refer to men with unfavorable risk intermediate- and high-risk cancer. Testing is aimed at diagnosing germline mutations in the BRCA family.
Diagnosing BRCA mutations has consequence for clinical management. Prichard and Nelson (NEJM. Aug 16) reported germline DNA repair gene mutations in 11.8% of men with metastatic disease including BRCA2, 5.3%; ATM 1.6% and BRCA1 0.9%. The effectiveness of PARP inhibition (using olaparib) in these men with metastatic disease was reported in NEJM 2015 by Mateo et al. showing an 88% greater than 50% PSA response in heavily pretreated men with metastatic prostate cancer harboring mutations in the BRCA 2 gene.
How to Learn Your BRCA Status?
If you have already engaged in ’23 and me’ or the ‘Gentleman’s Study” you already have partial BRCA 1 & 2 data, since those tests assess germline mutations.
‘Actionable’ mutations are those which adversely influence cell behavior and are vulnerable to therapeutic intervention, i.e PARP inhibitor therapy in BRCA mutation-positive men.
A second category of mutations is “somatic.” Somatic mutations are those which develop in the course of the disease as cells adapt to the stress of treatment with chemotherapy, radiation or potent androgen receptor inhibiting agents i.e., Zytiga and Xtandi.
The incidence of acquired somatic mutations increases to 20-30% in heavily treated men with metastatic disease and may offer additional ‘actionable’ mutations in the BRCA family which may be treated with PARP inhibitors. These mutations can be diagnosed by “liquid biopsy” of plasma assessing circulating tumor DNA. (ctDNA).
BRCA 1,2 and ATM mutations can be identified by submitting tissue to institutional pathology departments or commercial labs such as Foundationmedicine.com, which offers an expanded panel of several hundred genomic variations. The company also offers a limited panel, FoundationFocusCDxBRCA, which is a ctDNA panel analyzing for deleterious germline and somatic mutations in BRCA1 and 2. The University of Washington has an extensive panel (UW OncoPlex Cancer Gene Panel), but also offers the possibility of selecting 4 genes for analysis (which might be BRCA1, BRCA2, ATM, and CDK12).
A practical question is whether germline analysis (e.g., for saliva buccal scraping or from blood) captures all mutations of BRCA2 (the most prevalent mutation) or whether at the time of metastatic disease there is a need for additional analysis of somatic variants to capture the full range of BRCA mutations. Germline testing will detect 50% of the targetable DNA repair alterations (primarily BRCA1 or 2) in a man with prostate cancer.
Another practical question is whether sequencing tissue from prior prostatectomy or biopsy will detect mutations that are relevant to a man who developed advanced prostate cancer years later. Schweizer and Montgomery et al., (JAMA Oncol. June 2021), in an elegant example of genomic research, determined that most of the actionable mutations in BRCA2, ATM and CDK12 (a target for immune checkpoint inhibitor therapy) are present in primary tissue if they were found in metastatic biopsies or circulating tumor DNA.
Their conclusion: Sequencing of primary needle biopsies and prostatectomy specimens can find essentially all of the actionable alterations that can be used to prescribe PARP inhibitors.
How May PARP Inhibitor Therapy Be Sequenced in the Management of Prostate Cancer? The PROfound trial addressed this issue.
Conventionally, following initial therapy (surgery or radiation) when progression is declared at the rise of PSA to above 0.2 ng/mL, the first line systemic intervention is with hormone suppression (Lupron, Degarilix, Relugulix). When subsequent PSA progression occurs Zytiga, Xtandi or chemotherapy are considered in a variety of sequences.
The PROfound trial assessed men with mutations in BRCA 1,2 and ATM with non-metastatic cancer but rising PSA following treatment with either Zytiga or Xtandi when used as the second-line hormonal agent. One study group was randomized to olaparib and the other to either Zytiga or Xtandi, depending which agent has been used first and on which men had progressed. Olaparib was found to have superior benefit compared to either of the hormonal agents used as second-line treatment. The radiographic progression-free survival was 7.5 months for olaparib vs. 3.5 months for the alternate hormonal agent – either Zytiga or Xtandi. Thirty-three percent of men responded to olaparib vs. 2.3% to the second-line hormonal agent. (Confirming the known poor response to a second hormonal agent following a prior second-line hormonal agent.) The overall survival was 18 months for olaparib vs. ~14.5 months for men who were treated with the hormonal agent.
Olaparib Therapy in the Setting of Metastatic Disease.
The TOPARP trial studied heavily pretreated men harboring metastatic castration-resistant prostate cancer and compared the outcome of those men with BRCA 1/2 and ATM mutations to a matched cohort lacking these mutated genes. The mutational status was determined using FoundationFocus CDxBRCA analysis of circulating tumor DNA.
The benefit of the PARP inhibitor was evident: radiographic progression-free survival for olaparib in biomarker-positive men was 9.8 months vs 2.7 for those who were biomarker negative. Overall survival in biomarker-positive men was 13.8 months vs. 7.5 for those lacking BRCA mutations.
Clearly the message is: know your BRCA status ! When sequencing hormonal agents early in the course of prostate cancer or in the setting of metastatic disease PARP inhibition therapy in BRCA-positive men can offer significant benefit.