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    Association details:
    Biomarker:CDK12 mutation
    Cancer:Prostate Cancer
    Drug:Lynparza (olaparib) (PARP inhibitor)
    Direction:Sensitive
    Evidence:
    Evidence Level:
    Sensitive: A2 - Guideline
    Source:
    NCCN
    Published date:
    05/21/2020
    Excerpt:
    Olaparib is a treatment option for patients with mCRPC and a pathogenic mutaion (germline /somatic) in a homologous recombination repair gene (BRCA1, BRCA2, ATM, BADR1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L) who have been treated with androgen-receptor therapy.
    Evidence Level:
    Sensitive: B - Late Trials
    Source:
    ASCO-GU 2020
    Title:

    PROfound: Efficacy of olaparib (ola) by prior taxane use in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

    Published date:
    02/13/2020
    Excerpt:
    Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution.
    Trial ID:
    PROfound
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    The Study of Olaparib in Newly Diagnosed mCRPC Patients With HRR Gene Mutation

    Excerpt:
    ...- Qualifying HRR gene mutations (deleterious or suspected deleterious gene alterations) are BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L mutations confirmed by the central lab....
    Trial ID:
    PROspect
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis

    Excerpt:
    ...For enrichment stage of trial only (if necessary): Confirmation of a suspected/known deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) via CLIA certified testing....
    Trial ID:
    NCT03047135
    More C2 evidence
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

    Excerpt:
    ......
    Trial ID:
    BRCAAway
    Evidence Level:
    Sensitive: C2 – Inclusion Criteria
    New
    Source:
    clinicaltrials.gov
    Title:

    The Study of Olaparib Combined With Abiraterone and Prednisone in mHSPC Patients With HRR Gene Mutation

    Excerpt:
    ...- Qualifying HRR gene mutations (deleterious or suspected deleterious gene alterations) are BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L mutations confirmed by the central lab....
    Trial ID:
    NCT05167175
    Less C2 evidence
    Evidence Level:
    Sensitive: C3 – Early Trials
    Source:
    JCO Precis Oncol
    Title:

    CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

    Published date:
    04/21/2020
    Excerpt:
    CONTRADICTING EVIDENCE: Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months)….CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors.
    DOI:
    10.1200/PO.19.00399
    Evidence Level:
    Sensitive: C3 – Early Trials
    New
    Source:
    J Clin Oncol
    Title:

    TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.

    Excerpt:
    Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID...Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo).
    DOI:
    10.1200/JCO.2019.37.15_suppl.5005
    Trial ID:
    TOPARP
    Evidence Level:
    Sensitive: C4 – Case Studies
    Source:
    Mol Cancer Ther
    Title:

    A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE)

    Published date:
    02/10/2023
    Excerpt:
    We conducted a multicenter phase 1 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases....Nine patients were evaluable for HRR gene status; one had a BRCA2 alteration (rPFS 11.8 months) and one had a CDK12 alteration (rPFS 3.1 months).
    Secondary therapy:
    radium Ra-223 dichloride
    DOI:
    10.1158/1535-7163.MCT-22-0583