Pulling Back on "PARP Inhibitors"
- PARP inhibitors are a class of drugs that treat ovarian cancer at the genetic level.
- The official “standard of care” guidelines for PARPs for some indications are changing say experts. As always patients need to consult their doctors about the guidelines and treatment path that might be appropriate for them.
- Some PARP inhibitors could increase the risk of death in patients who've gone through several chemotherapies.
- For that reason, manufacturers of the three FDA-approved PARP-inhibitors have withdrawn their indications in the later line treatment setting for ovarian cancer.
- The FDA is restricting the use of PARP inhibitors for some indications because of recent studies that showed increased risk for death with these drugs when compared to regular chemotherapy.
- Ovarian cancer experts are discussing what the official indications for these drugs will be, given the rapidly changing landscape with the withdrawals.
Manufacturers of these three PARP-inhibitors have withdrawn their indications in the later line treatment setting for ovarian cancer. Moreover, the FDA is moving to further restrict the use of PARP inhibitors for some later-line indications because of recent data showing an increased risk for death with these drugs when compared to regular chemotherapy.Read More
“I sort of put it into baskets: I say PARP for treatment probably is unsafe for all people regardless of their genomic background. It doesn’t seem to be better than chemotherapy. PARP maintenance in the recurrent platinum sensitive setting is probably only safe for women that have a germline BRCA mutation. PARP maintenance for women in the upfront setting is still safe for all women as far as we know, but has the best responses and the best efficacy long-term in those that have BRCA gene mutation as well as possibly harboring HRD.”
It’s important to note that these withdrawals apply to late-line treatment indications for Lynparza, Zejula, and Rubraca, but do not affect other indications for PARP inhibitor maintenance treatment in ovarian cancer.
Several US ovarian cancer experts are currently discussing what the official indications for these drugs will be, given the rapidly changing landscape with the withdrawals. “I think all of us don’t know the future about whether or not in three years this conversation will be that really the only women that should be getting PARP inhibitors are women with BRCA gene mutations.” – adds Dr Growdon
PARP Inhibitors: Who Should Get It?
Below you can find the most up-to-date indications for PARP inhibitors. However, it’s vital to keep in mind that more changes will, most likely, occur in the upcoming months.
Newly-Diagnosed Advanced Ovarian Cancer
Currently, there is only one PARP inhibitor, Niraparib, which can be given to women regardless of BRCA or HRD status for maintenance therapy after initial diagnosis with an advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who have a complete or partial response to the usual choice for chemotherapy. Olaparib can be used for first-line maintenance of patients with BRCA mutation and with bevacizumab for patients with HRD or BRCA mutation.
“For women that have a germline or somatic BRCA mutations, I [discuss it as I did before and tell them], ‘It is probably one of the most important interventions we can offer to you. And it may be associated with prolonging your overall survival and maybe even has a, improves your chance of being cured of this,'” says Dr. Growdon. He continues, “For women with HRD, I have a similar conversation… I’m not sure if [PARPs are] going to improve [overall survival], but I do know that [they are] going to markedly change progression-free survival. The women [who take them] will be living longer without evidence of any resurgence.”
If you were recently diagnosed with advanced ovarian cancer and already responded to first-line chemotherapy, PARP inhibitors might be an option for you. First-line treatment or first-line therapy refers to the initial treatment. This treatment is usually what worked best in clinical trials for people with the same type and stage of cancer. After initial chemotherapy, studies now suggest that PARP inhibitors (such as Zejula or Lynparza in combination with bevacizumab for patients with HRD) can be an option for some ovarian cancer patients as a strategy to help reduce the risk of recurrence.
So, there's a lot of excitement about the use of these drugs as a maintenance therapy to stave off the disease. Maintenance therapy is a type of treatment that is given after chemotherapy and/or surgery to try to keep the cancer from returning. According to gynecological oncologists women should use a PARP inhibitor sooner rather than later in their line of treatment as a maintenance therapy. Maintenance therapy can be described as maintaining your remission or cancer-free period.
“[PARPs as] maintenance [therapy] in the upfront setting is still safe for all women… but [they have] the best responses and the best efficacy long-term in those that have a BRCA gene mutation as well as possibly harbor HRD,” summarizes Dr. Growdon.
Using PARPs to Treat Recurrence
Unfortunately, too often, ovarian cancer comes back. There was hope that PARP inhibitors could be used as a treatment (not maintenance) for recurrent cancers but some recent data have suggested that first-line maintenance and for selected patients second line maintenance therapy may be the best and only use of PARP inhibitor therapy.
For women with ovarian cancer who have had a recurrence, these drugs are now not recommended or approved as a third or fourth-line treatment for women with multiple recurrent ovarian, fallopian tube or primary peritoneal cancer. This means that if you have not received platinum-based chemotherapy prior to use, PARP inhibitor therapy cannot be suggested. It is now limited as a therapy for maintenance only.
In addition, Zejula can only be used as second-line maintenance for patients with BRCA mutation. It’s important to note that Zejula may still be used as a first-line maintenance therapy.
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 for all situations. You should ask your doctor if you are eligible for PARP inhibitors.
“PARP maintenance in the recurrent platinum-sensitive setting is probably only safe for women that have a BRCA mutation,” emphasizes Dr. Growdon.
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. However, the FDA has requested that Clovis Oncology limit the indication of Rubraca as second-line maintenance therapy in recurrent ovarian cancer. The proposed changes to Rubraca's label would limit its use to only patients harboring tumor BRCA mutations.
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 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 is a protein that works as a tumor suppressor. 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.
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
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
Dr. Growdon relates, “[Patients] would always feel like they’re fatigued. We would have to watch their labs. [They would have] more [office] visits, and more assessments with imaging.” However, for the appropriate patients, “[PARPs] can be a good choice that [are] worth the side effects,” he concludes.
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.