All About PARPS

Over the past few weeks many questions about PARP inhibitor use in the treatment ( front line, recurrent and maintenance) therapies for Ovarian Cancer were asked in many of the  private online groups that I participate in.  I can understand the questions and confusion because of the different PARPs available for women diagnosed with ovarian cancer - Olaparib ( Lynparza) , Niraparib ( Zejula) and Rucaparib (Rubraca) and their uses. 

In this blog post I will describe what a PARP inhibitor is, and provide all the FDA approval information and a few articles that compare the different types.

Let's start with this definition provided by the NCI.

PARP inhibitor
"A substance that blocks an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. DNA damage may be caused by many things, including exposure to UV light, radiation, certain anticancer drugs, or other substances in the environment. In cancer treatment, blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Also called poly (ADP-ribose) polymerase inhibitor."

I'm more a visual person so here is a video by Dana Farber that you might find helpful.




Now lets look at each PARP and when , who and why it was approved. The FDA pages include references to the clinical trials that the approval was based on. Remember there are still clinical trials enrolling that may use a PARP in combination with other treatments. 

Olaparib:Lynparza

2014 
FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. https://www.ncbi.nlm.nih.gov/pubmed/26187614

2017
On Aug. 17, 2017, the U.S. Food and Drug Administration granted regular approval to olaparib tablets (Lynparza, AstraZeneca) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-tablets-maintenance-treatment-ovarian-cancer

Prescribing info
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf

Niraparib:ZEJULA

2017
On March 27, 2017 , the U.S. Food and Drug Administration approved niraparib (ZEJULA, Tesaro, Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
https://www.fda.gov/drugs/resources-information-approved-drugs/niraparib-zejula

Here is additional information from an article in the AACR Journal
https://clincancerres.aacrjournals.org/content/24/17/4066

2019
On October 23, 2019,the Food and Drug Administration approved niraparib (ZEJULA, Tesaro, Inc.) for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status. HRD is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than six months after response to the last platinum-based chemotherapy.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-hrd-positive-advanced-ovarian-cancer

Rucaparib: Rubraca

2016

On December 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to rucaparib (RUBRACA, Clovis Oncology Inc.) for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.

https://www.fda.gov/drugs/resources-information-approved-drugs/rucaparib

2018
On April 6, 2018, the Food and Drug Administration approved rucaparib (Rubraca®, Clovis Oncology Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rucaparib-maintenance-treatment-recurrent-ovarian-fallopian-tube-or-primary-peritoneal

This NCI  blog post PARP Inhibitors as Show Promis as Initial Treatment for Ovarian Cancer pulls together the use of PARPs for initial treatment.
https://www.cancer.gov/news-events/cancer-currents-blog/2019/parp-inhibitors-ovarian-cancer-initial-treatment

While this 30 minute webinar is geared toward medical professionals, it provides an overview of all three PARP inhibitors and their use.

If you have other resources you would like to share on PARP inhibitors please leave a link the the comment section and I will update this page.

Dee
Every Day is a Blessing! 

How Do Those Ovarian Cancer Treatments Work?

I have always been interested in how cancer treatments work to destroy cancer cells. The other day I was talking to another ovarian cancer survivor on the phone. She was deciding between two treatments for a recurrence. When I hung up the phone I realized that I knew the side effects of the treatments but I really didn't know how they worked to kill off the cancer cells. So I decided to do some research on the NCI site to find the answer.

Here is a summary of the popular Chemotherapy treatments, drugs and biologics, used in the treatment of Ovarian Cancer. More complete information can be found at http://www.cancer.gov/drugdictionary

Paclitaxel ( Taxol) & Abraxane

“binds to and stabilizes microtubules,preventing their depolymerization and so inhibiting cellular motility, mitosis and replication”

Remember high school biology and the steps of cell reproduction. This drug affects that process. Abraxane is similar to Paclitaxel but does not use a solvent which causes side effects so it permits the administration of larger doses.

Carboplatin

“binds to GC-rich sites in DNA , thereby inducing intrastrand and interstrand DNA cross-link, as well as DNA-protein cross- links...results in apoptosis and cell growth inhibition.”

This platinum drug binds to the Guanine and Cytosine rungs on the DNA helix and causes cell growth to stop and then cell death occurs.

Gemcitabine ( Gemzar)

“is converted intracellularly to the active metabolites dFdCPD and dFdCTP... thereby decreasing the deoxynucleotide pool available for DNA synthesis and ... is incorporated into DNA , resulting in DNA strand termination and apoptosis.”

Inside the cell the drug is incorporated in its modified form into the DNA strands and leads to cell death.

Topotecan

“topotecan selectively stabilizes topoisomerase I-DNA covalent complexes, inhibiting religation of topoisomerase I-mediated single-strand DNA breaks and producing potentially lethal double-strand DNA breaks when complexes are encountered by the DNA replication machinery.”

Breaks in the strands of DNA caused by the topotecan prevents the DNA from replicating correctly and cell reproduction is inhibited.

Etoposide

“etoposide binds to and inhibits topoisomerase II and its function in ligating cleaved DNA molecules, resulting in the accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death.”

Etoposide causes breaks in the DNA thereby affecting cell reproduction and leads to cell death.

Bevacizumab ( Avastin)

“Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels.”

Cancer cells create blood vessels. Bevacizumab is a monoclonal antibody that binds to the vascular endothelial growth factor which helps create and maintain those cancer cell's blood vessels.

Dee

Every Day is a Blessing!

Genome Study and a Greater Understanding of Ovarian Cancer

I have wondered many times over the past 5+ years:

What makes my ovarian cancer tumor different than other women's tumors?

What about my tumor has allowed chemotherapy drugs to work effectively so that I would go in to remission, more than once? One possible answer might be the Selenium trial I was on.

Why do some women's tumors , even if they have the same subtype of OC, the same estrogen , progesterin analysis, still continue grow when exposed to the same chemotherapy?

Well, some of these questions have the potential for being answered. More than 500 ovarian serious adenocarcinoma tumors were examined as part of The Cancer Genome Atlas Research Network Study (TCGA). This was reported in the June 30th issue of Nature by the NCI.

What are some things they learn? Mutations in the gene TP53 which would normally prevent cancer from forming was found in 96% of the samples tested. The study found 68 genes that could be targeted for treatment by current FDA approved or experimental compounds. The study identified subtypes of the disease based on patterns in RNA transription from DNA. They also found that when the small molecule ( methyl compound) is added to the DNA the gene activity is affected.

I urge you to read this NCI press release and the summary in Nature for more information on what will definitely affect future areas of Ovarian Cancer Research.

Dee

Every Day is a Blessing!

OC Data - Surveillance Epidemiology and End Results

New Ovarian cancer data was released by the NCI.

"It is estimated that 21,880 women will be diagnosed with and 13,850 women will die of cancer of the ovary in 2010¹X Close
Table I-1 (http://seer.cancer.gov/csr/ 1975_2007/results_single/ sect_01_table.01.pdf)."
For more data click here.

Dee
Every Day is a Blessing!

NCI Bulletin- Risk of Ovarian Cancer from Hormone Therapy Confirmed

The NCI Bulletin discusses a Danish Study which confirms a risk of ovarian cancer for women who take hormone therapy. Read the entire article here. 

Avastin Increases Blood Clot Risk- NCI Bulletin

From the Nov 18, NCI Bulletin - Cancer Research Highlights

Bevacizumab May Increase Blood Clot Risk

"Bevacizumab (Avastin), the first FDA-approved drug designed to inhibit the growth of new blood vessels to tumors, significantly increases the risk of venous thromboembolism (VTE) in cancer patients, according to a meta-analysis in the November 19 Journal of the American Medical Association.

Pooled results from nearly 8,000 patients with a variety of advanced solid tumors in 15 randomized trials published since 2003 showed that patients taking bevacizumab were
33 percent more likely to develop VTE than those who did not. Incidence among those taking bevacizumab was 11.9 percent for VTE of all grades, and 6.3 percent for high-grade VTE. Those taking the drug had a 38 percent greater risk of developing high-grade VTE.

A dosage as small as 2.5 mg/kg per week was enough to pose a risk, which the authors believe "suggests that the so-called low dose of bevacizumab may already be reaching the saturation level to induce thrombosis." Based on the greater risk found in patients with mesothelioma and aerodigestive malignancies such as non-small cell lung cancer, the authors advised that patients with these conditions receive concurrent prevention for VTE.

"It may be appropriate to add a black box warning [to the package insert currently required by the FDA]," noted the study authors, led by Dr. Shobha Rani Nalluri and colleagues at Stony Brook University. Other angiogenesis inhibitors such as thalidomide and lenalidomide have also been shown to increase risk of VTE, and the authors warned that combining them with bevacizumab could compound the increased risk."

Avastin is not yet approved by the FDA for OC, but it is in use in a number of clinical trials.

LIVESTRONG
Dee