OLAPARIB and RUCAPARIB (PARP inhibitors): These newly FDA approved agents now offer a much needed additional treatment option for men with metastatic castration resistant prostate cancer (mCRPC). The prostate cancer field is abuzz with encouraging reports of efficacy of these drugs in patients who harbor adverse mutations in the BRCA gene family.

 An introduction to this topic was presented in the December 2019 PCa Commentary: “Clinical importance of genetic variants of BRCA 1/2 and ATM in men with metastatic castration resistant prostate cancer.” https://prostatecancerfree.org/pca-commentary-141 

In May 2020 both these drugs received FDA approval and are available for use in selected patients.

 Biology in brief:

 All cells, and especially cancer cells, when replicating frequently miscopy their genome creating disruptive mutations. The responsibility for correction falls upon two sets of DNA damage response genes, i.e., the BRCA family and the PARP (PolyAdenosine diphosphate Ribose Polymerase) system of enzymes 1, 2 & 3. When members of the BRCA family are mutationally dysfunctional the default for repair is the PARP enzymes. Inhibition of PARP by olaparib or rucaparib results in cell death.

 

The PROfound and TRITON2 Clinical Trials: The final results from these two trials led to FDA approval for both olaparib (Lynparza) and rucaparib (Rubraca) — and offer clinical guidance for sequencing drugs in treatment of mCRPC in men with mutations in the BRCA family of genes.

 

  • PROfound trial findings:  This randomized trial studied 245 men who had progressed on either Zytiga or Xtandi.  All men had mCRPC and were positive for mutations in BRCA 1,2, and ATM. The protocol randomized 162 men to therapy with olaparib  (300 mg orally twice daily) and 83 men to either Zytiga or Xtandi depending on which drug they had already taken (termed the ’switch’ arm). The trial end-point was time to radiographic progression.

 The median time for radiographic progression for olaparib was 7.3 months v. 3.5 in the switch arm, i.e., either Zytiga or Xtandi. As of March 2020 the preliminary median overall survival for olaparib was 19.1 v 14.7 months in the switch arm. This trial offered a ‘crossover’ to olaparib in those men who had progressed on the switch arm and 67% of progressers did switch to olaparib. The short duration of response to the second hormone suppressing agent in this study is in line with other studies showing a similar limited response to sequencing an alternative androgen receptor targeting agent after progression on the initial drug. For this reason, often chemotherapy is selected to follow progression on the initial agent, Zytiga or Xtandi.

  •  TRITON2 Clinical Trial:  A Phase II trial testing rucaparib (600 mg orally twice daily) in men with BRCA 1 and 2 alterations. This was a single arm study of 115 men with mCRPC and had a more stringent eligibility requirement than PROfound. These heavily pretreated men had progressed on either Zytiga or Xtandi and chemotherapy. This may explain its lower radiographic progression-free survival response rate of 44% as compared to 67% in the PROfound trial. The > 50% PSA response was 54.8%; preliminary median radiographic response duration was 9 months.

 

  •  Take Away Impression:  These two important trials jointly present a clinical implications: men with mCRPC with mutations in BRCA 1 and  2 (and to a lesser degree ATM) who progress on Zytiga or Xtandi experience improved survival if offered treatment with olaparib or rucaparib as opposed a second hormonal agent. 

 

How to determine your personal genomic profile of mutations.  There are at least 15 members of this family of DNA damage response mutations. The most prevalent being BRCA 2, followed next by a group including BRCA1, ATM, CHEK2 and PALB2.  In localized cancer ~6% of men carry BRCA1/2 and ATM mutations and in advanced disease the percentage rises to 10 -12 %.

 

First Definitions:  

 

  • Germline (inherited) mutations in DDR genes: These mutations are inherited and are found in all bodily cells, which is why a buccal smear, saliva, or blood cells can be analyzed. The Gentleman’s Study offers free analysis based on submission of saliva in men with metastatic prostate cancer. This is clinical trial, NCVT03503-97, with Dr. Heather Cheng, SCCA, as the principal investigator. 

 

  • Somatic (acquired) mutations in DDR genes: These are generated under the pressure of treatment, i.e. chemotherapy, androgen deprivation, radiation and can be found in ~ 25 – 30% of men with metastatic prostate cancer, increasing in prevalence with treatment intensity and duration.  Analysis for these mutations requires a fresh biopsy of a metastatic lesion, blood for circulating tumor DNA (ctDNA) or genetic analysis of circulating tumor cells. Analysis of somatic mutations will include the inherited mutations. Analysis of ctDNA is now regarded as yielding similar results as biopsy tissue.

 

  • Listed below are three FDA approved laboratories that analyze for ctDNA in “liquid biopsies” (i.e. blood). The WebSite for each includes background information, listing of special services and instructions how to submit a specimen.

 

      ** FoundationOne Liquid CDx (the companion test for the PROfound study) includes both germline and somatic mutations. Their analysis includes 324 genes, with 15 preselected for mutations in DDR genes

    ** Myriad Genetics. Their relevant test is termed ‘BRACAnalysis’ and includes 32 gene mutations in the DDR family.

  ** Guardant360 Cdx.  Their basic test includes 24 genes in the BRCA family.

 

BOTTOM LINE

 Why is this genetic information relevant to men with metastatic prostate cancer? 

Answer: awareness of harboring one of the mutations in the BRCA family makes a man eligible for olaparib or rucaparib (PARP inhibitors) as single agent therapy or as a participant in the many evolving protocols based on these drugs.

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