Pulling Back on "PARP Inhibitors"
- PARP inhibitors are a class of drugs that treat ovarian cancer at the genetic level.
- Almost all women are eligible to receive these drugs. However, women with the BRCA gene mutations seem to benefit the most from PARP inhibitors.
- Some PARP inhibitors could increase the risk of death in patients who’ve gone through several chemotherapies.
- Therefore, they are no longer indicated for patients who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with “HRD positive” status.
- These withdrawals as a treatment in later stage cancers are unlikely to have a great impact, because many oncologists worldwide are now using PARP inhibitors earlier rather than later.
“It’s probably one of the biggest advances we’ve had in the treatment of ovarian cancer in the last many years and we’re learning that they should be used earlier in the treatment course of a patient rather than later,” Dr Stephanie Gaillard, Director of Gynecologic Cancer Trials at Johns Hopkins, tells SurvivorNet.
Read MoreBut some studies have suggested that PARP inhibitors could actually increase the risk of death in patients who experienced several chemotherapies, forcing developers to withdraw their indications. However, these withdrawals of indication for later stages treatment will not have a great impact, because oncologists worldwide are using the PARP inhibitors at early phases, rather than later.
“Patients need to understand that most of the use of PARP inhibitors now is in maintenance frontline or second line, so while it's interesting, it kind of doesn’t really apply or affect how we’re currently using PARP inhibitors. It sounds bad [the withdrawals], but the reality is we don’t usually use PARP Inhibitors later line anymore anyway, because we’re using them so frontline,” says Dr. Chase
Zejula’s Withdrawal
Zejula can be an essential part of the maintenance treatment. However, its manufacturer (GlaxoSmithKline) told physicians in a letter that it has "voluntarily withdrawn" Zejula's fourth-line indication for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer and whose cancer is associated with homologous recombination deficiency (HRD) positive status. That means, for patients who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD positive status.
It's important to note that this change does not apply to any other Zejula's indications. That means that the drug can and should be used for the maintenance treatment of advanced epithelial ovarian cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
According to Dr. Ritu Salani, director of the Division of Gynecologic Oncology at UCLA, these withdraws will have minimal impact. “At this time, most, if not all, of these patients (BRCAm) will have received niraparib (or a PARP inhibitor) in the frontline setting for maintenance so this will not be an issue.”
Lynparza’s Withdrawal
Lynparza is no longer approved for use in highly pre-treated patients with advanced ovarian cancer harboring BRCA (a breast cancer gene mutation), which is actually two genes (BRCA1 and BRCA2), each are proteins that work as tumor suppressors. AstraZeneca and Merck withdrew Lynparza’s indication based on subgroup analysis of the phase III SOLO3 trial.
The results revealed that patients treated with Lynparza had a 33% greater risk of death than controls who received standard chemotherapy.
However, the withdrawal affects only patients who had undergone at least three prior lines of chemotherapy. It does not impact other existing indications for Lynparza and the drug remains approved for the first-line maintenance treatment of BRCA-mutated advanced ovarian cancer and for HRD-positive advanced ovarian cancer in combination with Genentech's Avastin.
Lynparza can also still be used as a maintenance medicine for recurrent ovarian cancer.
Rubraca’s Withdrawal
Clovis Oncology withdrew Rubraca’s indication for the tertiary treatment of ovarian cancer. A phase III clinical trial suggested that the risk of death increased by 31.3% in patients who had received two or more chemotherapies compared to existing chemotherapies in the ARIEL4 study.
This withdraw does not affect use of Rubraca in maintenance treatment of patients who are in response (complete or partial) to platinum-based chemotherapy.
PARP Inhibitors: Who Should Get It?
The FDA also approved the use of PARP inhibitors for the frontline treatment of ovarian cancer, as well as in the maintenance setting. These drugs have typically been most effective in women with certain genetic mutations or markers, including BRCA mutations and homologous recombination deficiency (HRD) a defect in the ability of a cell to repair its DNA.
The American Society of Clinical Oncology (ASCO) guidelines recommend PARP inhibitors be offered to women, with or without genetic mutations, who are newly diagnosed with stages III or IV ovarian cancer and have improved with chemotherapy.
One advantage to taking PARP inhibitors is their convenience, a term not often associated with the fight against cancer. "They're pills, so patients don't have to spend hours and hours in a chemotherapy infusion center," says gynecologic oncologist Dr. Saketh Guntupalli of the University of Colorado/Denver. "You take them at home. Oftentimes, with telemedicine, we're able to follow patients from afar, without them having to come in to the office. I keep patients on them as long as they can tolerate it. Generally, at about two years, we would consider taking the patient off because it's an expensive drug and they do have side effects."
Side Effects Of PARP Inhibitors
Unfortunately, like all cancer therapies, PARP inhibitors come with side effects. Whether or not you'll experience significant side effects from PARP inhibitors depends on several factors, including which PARP inhibitor you're taking, what dose you are ingesting, and whether you're using it alone or in combination with other therapies.
Still, the side effects of most PARP inhibitor protocols include:
- Nausea or vomiting
- Upset stomach
- Fatigue
These side effects can be intolerable for some patients, but in almost every case, doctors can offer options to alleviate or even eliminate them.
Since PARP inhibitors disrupt how cells repair damaged DNA, killing off tumor cells and healthy cells simultaneously, the bone marrow and blood cells may take a hit. As a result, a subset of patients encounter side effects of PARP inhibitor treatment related to bone marrow suppression such as reduced blood cell and platelet counts.
- Anemia (a drop in the red blood cells), which may result in fatigue
- Thrombocytopenia (a drop in the platelet count), which can cause easy bruising and excessive bleeding
- Neutropenia (a drop in the white blood cell count), which can leave people more susceptible to infection
Education and transparent provider-patient discussions about PARP-inhibitor eligibility, as well as the side effects and high prices associated with these drugs, can make a dramatic difference in treatment results. No two cancers are the same, and every patient has a different level of tolerance for side effects and financial burdens. So, although PARP inhibitors are giving many women with ovarian cancer a tremendous amount of hope, they shouldn't be universally prescribed.
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