In the U.S., 80% of patients with ovarian cancer are diagnosed at stage 3 or 4 – advanced cancers that have spread beyond the ovaries to lymph nodes or organs outside the pelvis. Approximately half of these cancers are associated with a condition called Homologous recombination deficiency (HRD), when the cancer cells are unable to repair breaks in their DNA. BRCA-1 and BRCA-2 mutations are two genes that are involved in homologous recombination.
Patients who undergo aggressive treatment – surgery, chemotherapy, and/or radiation – for advanced ovarian cancer face a 70%-90% risk of recurrence after initial treatment.
A new approach is proving to be an exceptional counterstrike. Poly ADP-ribose polymerase 1 (PARP-1) inhibitors work by stopping cancer cells with damaged DNA from repairing themselves and replicating – thus reducing the risk of recurrence after HRD- or BRCA-associated ovarian cancer by 40-70%.
Several PARP-1 inhibitor drugs are currently available for patients with ovarian cancer. Each drug works differently, and patients need a personalized approach to find the appropriate drug and dosage to achieve maximum benefit.
Right now, these drugs only help about 50% of patients with ovarian cancer who have completed initial treatment with surgery and chemotherapy – those with HRD or BRCA mutations. UT Southwestern is leading research to find more biomarkers and targetable PARPs and extend effective maintenance to patients with other forms of ovarian cancer.
While no cancer maintenance drug can claim 100% cancer freedom, early data show PARP-1 inhibitor drugs to be a highly effective personalized and targeted therapy. Clinically, that translates to less cancer risk. Individually, patients get longer, higher-quality years of life after the physical and emotional strains of surviving cancer.
Eligibility starts in the tumor genes … and germline
Every patient who has ovarian cancer should be referred for genetic testing, which should include somatic and germline testing. Somatic (tumor) testing identifies changes present only in the cancer cells, whereas germline testing determines whether healthy cells carry a specific, potentially harmful genetic mutation.
Both tests are important because some tumors have genetic mutations that do not appear elsewhere in the patient’s body – the tumor, not the patient, is the carrier of the cancer-associated mutation. This can happen if the cancer cells are genetically unstable and likely to mutate. Nearly half of all ovarian cancers have faulty DNA repair pathways.
UT Southwestern’s Simmons Comprehensive Cancer Center takes genetic testing a step further by analyzing tumors for mutations. If genetic or germline testing reveals a BRCA mutation or HRD, the patient may be eligible for a PARP-1 inhibitor maintenance medication after cancer treatment.
Taking a PARP-1 inhibitor: What to expect from the medication
PARP-1 inhibitor drugs are oral medications that patients take daily. These drugs are generally well-tolerated. Some patients experience mild side effects such as nausea, loss of appetite, and fatigue. Fewer patients experience a decrease in white blood cells that help the body fight infection. In approximately 1%-2% of patients, this leads to acute myeloid leukemia, a cancer that occurs when bone marrow produces abnormal blood cells.
Because of these risks, patients will need to visit their doctor weekly and then monthly to get lab work and evaluate whether their dosage is appropriate. Often, we see patients for a second opinion if they are struggling with side effects and dosage from their current PARP-1 inhibitor medication.
Every patient responds differently to medications, depending on their general health after treatment and underlying conditions. We give patients options and information to help them choose a maintenance care plan they are comfortable with to safely and effectively support their health goals.
Extending the benefits of PARP inhibitor therapy
We continue to study new ways to extend effective PARP maintenance therapy options to the 50% of ovarian cancer patients who do not have a BRCA mutation or HRD.
In a translational study I conducted with W. Lee Kraus, Ph.D., Director of the Cecil H. and Ida Green Center for Reproductive Biology Sciences, we found additional biomarkers that may help us predict sensitivity to PARP inhibitors. One biomarker, ADP-ribosylation, allows us to better categorize the tumor and its sensitivity to PARP inhibitors, regardless of HRD or BRCA 1/2 status. This research could help us identify who might benefit most from a PARP inhibitor drug and reduce ovarian cancer recurrence risk in more patients.
We are also working to identify other PARP enzymes that we could potentially target to further improve patient outcomes. PARP-16, for example, uses a cell substance called NAD+ to change ribosomes, which synthesize proteins in our cells. If a PARP-16 inhibitor were developed, we could target and stop this reaction, stunting cancer recurrence for even more patients.
Going through cancer treatment can take a toll on the body and mind. Once you successfully enter treatment, PARP therapy may be an effective way to keep recurrence at bay. For a growing number of patients, a daily pill can decrease cancer recurrence risk by up to 70%, offering less stress and more happy, healthy years after treatment.