September 16, 2022
Contributed by Dr. Rodrigo C. Leão Edelmuth, MD, Medical Fellow at SurvivorNet.
Good news for women with ovarian cancer has just emerged from the European Society for Medical Oncology (ESMO) Annual Meeting: positive long-term data from two phase III trials of Olaparib (brand name Lynparza) maintenance treatment in patients with newly diagnosed advanced (stages III or IV) ovarian cancer. Maintenance therapy is a type of treatment that is given after chemotherapy and/or surgery to try to keep the cancer from returning.
The trials found that the combination of two drugs (Lynparza and Avastin, also known as bevacizumab) may cut the risk of death by 38 percent. The data was based on results from a phase III clinical trial called PAOLA-1, and it revealed that women with ovarian cancer whose tumors were positive for a biomarker known as homologous recombination deficiency (HRD) could benefit from this drug combination.
An estimated 65.5 percent of Lynparza-Avastin takers are expected to be alive in five years, versus 48.4 percent for those only taking Avastin, according to investigators’ analysis of the phase III PAOLA-1 trial. The patients in the trials received the combo in the first-line maintenance setting after responding to a round of chemotherapy.
SurvivorNet spoke to Dr. Stephanie Wethington, an assistant professor of the Johns Hopkins Department of Gynecology and Obstetrics, who agreed with the importance of this new study. “The SOLO-1 [trial] is practice changing. The overall survivor data, which is what was presented at ESMO, is compelling and hints that waiting, ie treating at recurrence, is not as effective,” she said.
What are PARP Inhibitors?
Lynparza is a PARP inhibitor. The poly (ADP-ribose) polymerase, or PARP inhibitor drugs are relatively new to cancer care. These drugs, which are taken orally, work by preventing cancer cells that have been damaged, often by chemotherapy, from being able to heal themselves. PARP inhibitors have typically been used as maintenance therapy, to prevent a recurrence of cancer after a woman has already had surgery and traditional chemotherapy. When used this way, PARP inhibitors can potentially prolong remission and prevent disease recurrence for long periods of time – maybe even indefinitely.
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.
Homologous Recombination Deficiency (HRD)
HRD is a genetic factor, sometimes present in the tumors of women who have mutations in the BRCA gene. HRD means that a woman’s ovarian cancer cells have trouble repairing themselves. And this can make them somewhat easier to fight. Ovarian cancer patients with homologous recombination deficiencies exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and PARP inhibitors, according to researchers. This means that women with the BRCA gene and HRD may benefit more from certain chemotherapy drugs and the cancer-attacking school of drugs known as PARP inhibitors.
“Fifty percent of ovarian cancer are characterized as HRD. That’s that’s pretty common. One out of two chance that you have this biomarker, which could impact your treatment choices. And also could help you to understand what your chances are of potentially surviving,” Dr. Dana Chase, a Gynecologic Oncologist at the Virginia G. Piper Cancer Care Network, told SurvivorNet
The BRCA mutations (BRCA1 and BRCA2) are the most important genetic biomarker for ovarian cancer. These genes help repair damaged DNA, and are important for ensuring the stability of each cell’s genetic material. When they are mutated, they may contribute to the development of early ovarian cancer in younger women.
“BRCA mutations are the most commonly known and probably one of the first that were discovered in ovarian cancer to lead to what we call homologous recombination deficiency which is the inability to repair double strand breaks. There are other genes that are in that same pathway that lead to the same problem.” Dr. Rebecca Arend, gynecologic oncologist at the University of Alabama Comprehensive Cancer Center, told SurvivorNet in a previous conversation.
Improving Progression-Free Survival
The PAOLA-1 trial presented at the European Society for Medical Oncology (ESMO) Annual Meeting was published on the European Cancer Journal. The study, which was conducted in 11 countries, evaluated the combination of Lynparza and Avastin on newly diagnosed, advanced (stages III or IV), high-grade ovarian cancer.
Women in the trial had all been treated with chemotherapy and Avastin, and then they either continued receiving Avastin with a placebo (inactive treatment), or with Lynparza.
The results showed that the greatest benefit was in patients with a BRCA mutation or HRD who received the combination of drugs. In patients with HRD-positive tumors who received Avastin plus Lynparza, the progression-free survival (that’s the time a relapsed patient’s cancer goes without growing) was just over 50 months, compared to 35.5 months in the group that received the placebo along with Avastin.
“We are seeing some tremendous progression-free survival benefits, and potentially almost a doubling of the progression-free survival,” Dr. David Engle, a gynecologic oncologist with the Baptist Medical Group in Memphis, told SurvivorNet in a previous conversation.
The researchers also demonstrated that the combination of Lynparza and Avastin may cut the risk of death by 38% in newly diagnosed advanced (stages III or IV) ovarian cancer patients. Overall survival refers to the length of time that someone lives after starting a specific treatment. A clinical trial that tested your treatment for efficacy (how well it worked), for instance, might tell you what the “median overall survival” was—meaning the median length of time that the patients who got that specific treatment went on to live.
The SOLO-1 Phase III trial demonstrate that lynparza provided a meaningful improvement in overall survival (OS) versus placebo in patients with BRCA-mutated newly diagnosed advanced ovarian cancer, reducing the risk of death by 45 percent. At the seven-year analysis, 67% of lynparza patients were alive versus 47% of placebo patients. They also demonstrated that 45 percent of lynparza patients versus 21% of placebo patients were alive and had not received a first subsequent treatment. These data provide the longest follow-up for any PARP inhibitor in this setting and support use of maintenance olaparib to achieve long-term remission and enhance the potential for cure.
Additional data showed median time to first subsequent therapy was 64 months with lynparza versus 15.1 months with placebo. The safety and tolerability profile of lynparza in this trial was in line with that observed in prior clinical trials, with no new safety signals.
“Achieving long-term survival for patients with newly diagnosed advanced ovarian cancer is critical because the first-line setting offers the greatest potential to impact patient survival,” Dr. Paul DiSilvestro, investigator from the SOLO-1 trial, said in a statement. Dr DiSilvestro is director of the Program in Women’s Oncology for Women & Infants Hospital of Rhode Island and Care New England Health System.
PARP Inhibitors Side-Effects
PARP inhibitors’ effects on the blood are among the most concerning to doctors. These drugs disrupt how cells repair damaged DNA, killing off tumor cells, but also some healthy cells as well. Bone marrow activity may be affected, which is why healthy blood counts–red blood cells, white blood cells, and platelets — may be diminished.
Hematologic (blood-related) side effects can include:
- 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
In both trials presented, the safety data are encouraging. “One of the concerns with PARP inhibitors is the small risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML), particularly in patients with a BRCA mutation. The low levels of MDS and AML in both trials with longer follow-up is reassuring.” said Prof. Jonathan Ledermann, from UCL Cancer Institute, London, UK, at ESMO 2022.
Should PARP Inhibitors Be Prescribed to Everyone?
If your doctor does not bring up PARP inhibitors early-on during the course of your treatment, you should absolutely ask! Having this conversation could be vital to your long-term and progression-free survival.
With the promising outcomes for those treated with PARP inhibitors, doctors are recognizing a huge curative potential for these new drugs.
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.
The term ovarian cancer refers to a number of different tumors that grow in the ovary. The ovaries produce the sex hormone, estrogen, as well as eggs. Every woman has two ovaries, one on either side of her uterus.
Different ovarian cancers occur in women at different points of life, with most occurring post menopause. According to Dr. Beth Karlan, gynecological oncologist at UCLA medical center, “The most common type of ovarian cancer, however, typically occurs around the time of menopause, in the fifth decade.” In fact, about half of ovarian cancers occur in women over age 60, and they are often diagnosed at later stages. In terms of total risk, one woman out of every 71 (approximately 1.4%) will develop ovarian cancer at some point in her lifetime, according to the American Cancer Society. Ovarian cancers, like so many other cancers, are best and most easily treated if caught early.
There isn’t just one ovarian cancer; there are many different types that occur at different stages of life. In fact, researchers have identified over 30 types, but these three are the most common:
- Epithelial: About 90% of ovarian cancers are epithelial, which means the cancer cells are located on the outer layer of the ovary. Most epithelial tumors are not cancerous, but when they are cancerous, they can spread before they are detected.
- Stromal: This rare type of tumor forms in the connective tissue that holds the ovary together and produces estrogen and progesterone.
- Germ cell: These tumors, which develop in the cells that produce the eggs, are more likely to affect a single ovary, rather than both ovaries. When a teen or young woman is diagnosed with ovarian cancer, it’s usually the germ cell type. The good news is that most women with these types of ovarian cancers can be cured.
Clinical Trial Phases
There are four different phases in an interventional cancer clinical trial, each having a specific goal to establish. These phases can be summarized through the following points:
- Phase I. The first phase of the trial is initiated after a drug is approved and aims to find a safe dose for and determine the optimal method for drug administration. This phase involves a small number of volunteers (15-30 participants).
- Phase II. The second phase of the trial is initiated after a safe dose of the drug has been determined from the first phase, and it aims to test the effectiveness of the treatment. This phase involves around 100 volunteers or less.
- Phase III. In stages I and II, a drug has shown promising results. Phase III is initiated on a much larger scale and aims to compare a new treatment with traditional treatments. This phase involves from one hundred to several thousand volunteers.
- Phase IV. This phase starts after the approval of the drug and lasts for several years to make sure that there are no long-term effects or adverse events for the drug that hasn’t been shown in the previous phase. This phase is also known as the post-marketing phase.