Ovarian Cancer, BRCA & PARP Inhibitors

Guidelines recommend germline genetic testing for everyone diagnosed with ovarian, fallopian tube or primary peritoneal cancer. Age and family history do not change that. It is one of the few cancers where testing is recommended for everyone.

There are two reasons. The first is treatment. BRCA status helps show whether a PARP inhibitor is likely to help. The second is family. An inherited BRCA variant means each child, sibling and parent has a 50% chance of carrying it. They can then be tested for that specific change.

Testing often happens in two places at once, and the difference matters:

• Germline testing uses blood or saliva and finds inherited variants. These affect relatives.
• Somatic (tumor) testing reads the tumor's DNA. A BRCA change found only in the tumor arose during your lifetime and is not passed on, though it can still make a PARP inhibitor appropriate.

Both can point to the same drug. Only the germline result says anything about your family.

Cancer cells with faulty BRCA genes have already lost one major DNA repair route. PARP inhibitors block another one. With both gone, the cell builds up damage it cannot fix, and it dies. Healthy cells have working BRCA genes, so they are far less affected.

Three PARP inhibitors are used in ovarian cancer: olaparib (Lynparza), niraparib (Zejula) and rucaparib (Rubraca).

PARP inhibitors are mostly used as maintenance therapy. That means they start after platinum-based chemotherapy has finished and produced a complete or partial response. The aim is to hold the cancer back and delay its return. The aim is not to shrink it in the first place.

They are daily tablets or capsules taken at home. Many people take them for a set period, such as two years, or until the cancer progresses.

SOLO-1 tested olaparib maintenance after first-line chemotherapy in women with BRCA-mutated advanced ovarian cancer. Three years in, 60% of the olaparib group were free of progression, compared with 27% on placebo. That is a 70% reduction in the risk of progression or death. Median progression-free survival on placebo was around 14 months.

PRIMA tested niraparib in a broader group. In HRD-positive tumors, median progression-free survival was 22 months versus 10 months. In HRD-negative tumors it was 8 versus 5 months.

PAOLA-1 tested olaparib added to bevacizumab. In HRD-positive tumors, median progression-free survival was 37 months versus 18. In HRD-negative tumors there was no meaningful difference.

The pattern is consistent. The benefit is largest with a BRCA variant. It is still there with HRD. It is small or absent without either.

Homologous recombination deficiency (HRD) describes tumors that cannot repair one particular kind of DNA damage. BRCA mutations are one cause. Other genes can produce the same weakness, as can a characteristic pattern of genomic scarring.

HRD is defined as the presence of a harmful BRCA mutation, or a qualifying score on a molecular test of the tumor. About one in three ovarian cancers is HRD. Testing for it helps predict who will benefit when no BRCA variant is found.

The most common problems are low blood counts — anemia and low neutrophils. Nausea and fatigue are common too. Niraparib can also raise blood pressure. Doses are often adjusted rather than stopped. In SOLO-1, 12% of participants stopped because of side effects.

Blood counts are monitored throughout. One reason is that a small number of people go on to develop myelodysplastic syndrome or acute myeloid leukemia. In SOLO-1 this occurred in about 1%.

Some later-line indications were withdrawn after longer follow-up. In those settings, PARP inhibitors were used to treat recurrent disease after several rounds of chemotherapy. The maintenance indications remain.

If you have read older material, it may describe uses that are no longer approved. Ask your oncologist which setting your own recommendation falls into, and what the goal of the drug is in your case.

• Call 911 or go to an emergency department if breathlessness arrives suddenly, or chest pain grips when you breathe in. The olaparib label warns of clots in the lungs and legs.
• Ring your oncology team the moment it happens, at any hour, if your temperature reaches 100.4°F (38°C), or you go shivery and unwell, while you are on one of these tablets. They push neutrophils down, and CDC treats a fever during cancer treatment as a medical emergency rather than something that can wait for morning. If the line does not get you help quickly, go to an emergency department and say you are on cancer treatment.
• Call your oncology team the same day if a cough or breathlessness is new or worsening without a fever. The label says treatment is held while lung inflammation is ruled out.
• Call your oncology team within a day or two if home blood pressure readings climb on niraparib, or if breathlessness on stairs, a racing pulse or unusual paleness suggests the anemia described above is deepening.

• FDA — LYNPARZA (olaparib) Prescribing Information
• NCI — PARP Inhibitors as Initial Treatment for Ovarian Cancer (PRIMA, PAOLA-1, VELIA)
• NCI — Olaparib Maintenance Therapy Delays Ovarian Cancer Progression (SOLO-1)
• NCI — BRCA Gene Changes: Cancer Risk and Genetic Testing
• CDC — Fever During Cancer Treatment