PARP Inhibitors - Effective in Men with BRCA-Mutant Prostate Cancer
by Dr. C.H. Weaver M.D. updated 6/2020
Precision cancer medicines known as PARP Inhibitors are increasingly used to treat women with ovarian or breast cancer with specific genomic defects that prevent them from repairing DNA which results in cancer. Approximately 1 in 4 men with prostate cancer appear to have similar defects in DNA repair and can benefit from treatment with a PARP Inhibitor.
The PARP Inhibitors Rubraca® (Rucaparib) and Lynparza (olaparib) have been demonstrated to delay the progression of prostate cancer in men with refractory cancer. All men should should undergo genomic testing to determine whether PARP inhibitors play a role in the management of their cancer.
About PARP Inhibitors
PARP inhibitors are precision cancer medicine that block DNA damage response (DDR) in cancers harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2.
The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.
Lynparza was the world’s first drug to reach the market targeted against inherited cancer mutations, and was found to benefit as many as a third of patients with prostate cancer, including many who did not inherit cancer genes but whose cancers had acquired defects in DNA repair according to initial study results released in the New England Journal of Medicine in 2015.
Rubraca is the first PARP inhibitor approved in a prostate cancer setting. The U.S. Food and Drug Administration (FDA) approved Rubraca® for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. (7,8) The FDA approval for for Rubraca is based on data from patients with mCRPC and a deleterious BRCA mutation enrolled in the multi-center, single arm TRITON2 clinical trial. Rubraca...
- Produced a 44% overall response rate - rates were similar for patients with germline and somatic BRCAm.
- Achieved a 55% PSA response rate.
- The median duration of response had not been reached at the time of reporting with responses ranging from 2 to > 24 months
In the initial trial evaluating Lynparza 49 men with treatment-resistant, advanced prostate cancer received Lynparza, and 16 of them (33%) responded, as defined by a set of clinical criteria. Lynparza stopped prostate cancer growth, generating lasting falls in prostate specific antigen (PSA) levels, falls in circulating cancer cell counts in the blood, and radiological responses on CT scans and MRI.
The clinical trial found that up to 30% of men with advanced prostate cancer with defects in their systems for repairing DNA detected by genomic testing – and that these responded particularly well to Lynparza.
The results of the trial led to the TOPARP-B clinical trial in which only men whose prostate cancers had detectable DNA repair mutations were treated with Lynparza. All men enrolled in the trial had advanced diseased that had progressed on androgen deprivation therapy, 99% had received Taxotere, 90% Zytiga, Xtandi, and 38% Jevtana.
The overall response rate to treatment was 54% in 98 men with DNA repair mutations. Among 30 men with confirmed mutations in BRCA 1/2 alterations, 83.3% responded to treatment, and 57.1% with PALB2 alterations responded to the treatment. Lynparza delayed cancer progression an average of 5.5 months
The PROfound Clinical Trial in Castrate Resistant Prostate Cancer
The PROfound clinical trial evaluated the effectiveness and safety of Lynparza compared with Xtandi (enzalutamide) or Zytiga (abiraterone) in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on prior treatment with new hormonal anticancer treatments and had a qualifying genetic mutation in one of 15 genes involved in the HRR pathway, including among BRCA1/2, ATM and CDK12.(3)
Results from the trial showed that Lynparza delayed cancer progression compared to Xtandi or Zytiga in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations and further confirm the value of performing genomic testing in men with advanced prostate cancer. Updated trial results published in April 2020 revealed that the Lynparza associated delay in cancer progression led to improved overall survival which led to FDA approval for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic mCRPC, who have progressed following prior treatment with Xtandi or Zytiga.
Approximately 1 in 3 men with refractory prostate cancer have alterations in one or more genes linked to repairing damaged DNA. BRCA mutations are by far the most common and were found in 33% of the cancers with a DNA repair mutation. Other common DNA repair mutations were the genes ATM, CDK12, CHEK2 and PALB2.
Results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) with Lynparza versus Xtandi or Zytiga in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations. ()
Understanding HRR gene mutations
HRR mutations occur in approximately 20-30% of patients with mCRPC. (4) HRR genes allow for accurate repair of damaged DNA in normal cells. (5,6) HRR deficiency (HRD) means the DNA damage cannot be repaired, and can result in normal cell death. (6) This is different in cancer cells, where a mutation in HRR pathways leads to abnormal cell growth and therefore cancer. (6) HRD is a well-documented target for PARP inhibitors. PARP inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks, which in turn lead to cancer cell death. (6)
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England Journal of Medicine. 373:1697-1708. October 29, 2015,
- Lynparza Phase III PROfound trial in HRR* mutation-selected metastatic castration-resistant prostate cancer met primary endpoint
- Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. New England Journal of Medicine, 373(18), pp.1697 - 1708.
- Li et al. (2008). Homologous recombination in DNA repair and DNA damage tolerance. Cell Research, 18(1), pp.99-113.
- Ledermann et al. (2016). Homologous recombination deficiency and ovarian cancer. European Journal of Cancer, 60, pp.49-58.
- FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer
- ESMO 2019: Preliminary Results from the TRITON2 Study of Rucaparib in Patients with DNA Damage Repair-deficient mCRPC: Updated Analyses
- FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer