by Dr. C.H. Weaver M.D. updated 3/2019
There is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with the same type of cancer, the behavior of the cancer and its response to treatment can vary widely. By exploring the reasons for this variation, researchers have begun to pave the way for more personalized cancer treatment. It is becoming increasingly clear that specific characteristics of cancer cells and cancer patients can have a profound impact on prognosis and treatment outcome. Although factoring these characteristics into treatment decisions makes cancer care more complex, it also offers the promise of improved outcomes.
Not all cancer cells are alike
Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy”
Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
By testing an individual’s ovarian cancer for specific unique biomarkers doctors continue to develop new precision medicines. Individuals not previously tested undergo genomic testing to determine whether newer precision cancer medicines are a treatment option.
PARP Inhibitors for Ovarian Cancer with BRCA Mutations
The poly ADP-ribose polymerase (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.(1,2,3)
PARP inhibitors have the greatest effect in women with mutations of the BRCA genes but may benefit additional patients with different genetic profiles as well. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers.
The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10 to 15 percent of all ovarian cancer is associated with these hereditary BRCA mutations.
LynparzaTM (olaparib); constitutes the first PARP inhibitor approved for treating ovarian cancer. Lynparza was approved for patients with specific abnormalities in the BRCA gene.1 The FDA approved Lynparza with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer.
Zejula (Niraparib): when used as maintenance therapy following platinum-based chemotherapy appears to improve the time to cancer progression among patients with recurrent ovarian cancer. Patients with BRCA 1 and BRCA 2 germline mutations appear to derive the greatest benefit from Zejula.
Researchers reported the results of approximately 500 women who had responded to platinum-based chemotherapy for recurrent ovarian cancer who were then treated with Zejula.(3)
One group of patients in the trial had a BRCA1 or BRCA2 germline gene mutation, which predisposes individuals to a significantly increased risk of developing ovarian cancer within their lifetime; one group of patients had without germline BRCA1 or BRCA2 mutations; and one group of individuals had neither BRCA1 or BRCA2 germline mutations nor HRD.
- Among patients with germline BRCA 1 or 2 mutations, median survival time without progression of cancer (progression-free survival, PFS) was 21 months among patients treated with Zejula, compared with only 5.5 months for those who received placebo.
- Among patients without germline BRCA1 or 2 mutations who were homologous recombination deficiency (HRD) positive, the median PFS was 12.9 months for those treated with naraparib, compared with only 3.8 months for those who received placebo.
- Among patients without germline BRCA1 or 2 mutations who had either HRD-positive or HRD-negative cancers, median PFS was 9.3 months for those treated with naraparib, compared with 3.9 months for who received placebo.
Rubraca™ (rucaparib): In patients with BRCA - positive ovarian cancer that had returned after previous treatment more than half of the patients treated with Rubraca responded to treatment for an overall response rate of 65%. Patients who had the longest time to cancer progression before the study had the highest response rates. The ARIEL clinical trial demonstrated that Rubraca® treated patients survived on average 13.7 months without cancer progression compared to 5.4 months for those not receiving Rubraca® leading to FDA approval as maintenance therapy.(4)
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.
The rationale for combining a PARP and checkpoint inhibitor in ovarian cancer comes from pre-clinical evidence that PARP inhibition increases PD-L1 expression, and that increased PARP inhibitor–induced DNA damage might enhance immune recognition.
Currently available checkpoint inhibitors:
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
What do the studies show?
- Keytruda-Zejula combination appears promising
- Lynparza-Imfinzi combination in platinum sensitive ovarian cancer
- Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Journal of Clinical Oncology. 33, 2015 (supplement; abstract 5513).
- Tesaro Inc., press release. Tesaro’s niraparib significantly improved progression-free survival for patients with ovarian cancer in both cohorts of the phase 3 NOVA trial. Available at: . Accessed July 6, 2016.
- U.S. Food and Drug Administration. (2016.) FDA grants accelerated approval to new treatment for advanced ovarian cancer. [Press release.
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