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Olaparib significantly prolongs PFS in metastatic BRCA–related breast cancer
CHICAGO — Olaparib significantly prolonged PFS compared with chemotherapy among patients with HER-2–negative metastatic breast cancer and germline BRCA mutations, according to results of the randomized phase 3 OlympiAD trial presented at the ASCO Annual Meeting.
Olaparib (Lynparza, AstraZeneca), a PARP inhibitor approved for use in women with BRCA–related ovarian cancer — also significantly extended time to second progression.
“It is our opinion that olaparib can be an effective treatment option for women with BRCA mutations and metastatic HER-2–negative breast cancer — importantly, including women with BRCA mutations and triple-negative disease,” Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation. “This type of breast cancer is particularly difficult to treat and often affects younger women.”
Up to 3% of breast cancers occur among women with inherited changes in BRCA1 and BRCA2 genes. These changes reduce a cell’s ability to repair damaged DNA.
Olaparib blocks PARP1 and PARP2, enzymes that are involved in DNA repair. Cancer cells with BRCA mutations are especially vulnerable to therapies that target PARP.
“If you inhibit PARP 1 and PARP 2, you create damage that requires [a repair pathway] to fix it,” Robson said. “Cells that are defected in the [repair pathway] — and those that have BRCA mutations are the best-known examples of that — are actually sensitive to drugs that inhibit PARP. If you give a PARP inhibitor, the enzyme gets stuck on the DNA and creates a lesion that has to be repaired by BRCA1 and BRCA2. In the cancer from the patient that has an inherited BRCA mutation, when the PARP gets trapped, that lesion can’t get resolved.”
Robson and colleagues conducted OlympiAD to assess the efficacy and safety of olaparib compared with standard single-agent chemotherapy of physician’s among patients with HER-2–negative metastatic breast cancer that either was hormone receptor–positive or triple negative. The analysis included 302 patients (median age, 44 years), all of whom harbored germline BRCA mutations. Fifty percent had triple-negative disease; 71% had undergone up to two rounds of prior chemotherapy for metastatic breast cancer; and 28% had received prior platinum. Those with hormone receptor–positive disease received prior hormonal therapy.
Researchers randomly assigned patients 2:1 to olaparib 300 mg twice daily (n =205) or physician’s choice of standard chemotherapy, which consisted of 21-day cycles of capecitabine, vinorelbine or eribulin (n = 91). Six patients did not receive treatment.
Therapy continued until objective disease progression or unacceptable toxicity.
PFS served as the primary endpoint.
A higher percentage of patients assigned olaparib experienced tumor shrinkage (60% vs. 29%).
At median follow-up of about 14 months, olaparib-treated patients experienced significantly longer median PFS (7 months vs. 4.2 months; HR = 0.58; 95% CI, 0.43-0.8).
Olaparib also extended time to investigator-assessed second progression (HR = 0.57; 95% CI, 0.4-0.83) and increased objective response rate (59.9% vs. 28.8%).
Olaparib-treated patients experienced fewer grade 3 or worse adverse events (36.6% vs. 50.5%), as well as fewer adverse events that required treatment discontinuation (4.9% vs. 7.7%).
The most common adverse events among olaparib-treated patients included nausea and anemia. The most common adverse events among chemotherapy-treated patients included low white blood cell counts, anemia, fatigue, and rash on the hands and feet.
Researchers reported significantly better health-related quality of life in the olaparib group.
The study is not mature enough to determine whether olaparib extends OS in this patient population.
This is the first of four phase 3 clinical trials of PARP inhibitors in breast cancer to report findings. More research is needed to determine olaparib’s effectiveness in cancers that worsen despite platinum-based chemotherapy — a standard regimen not included in this study — and whether platinum-based chemotherapy would be useful after cancers worsen despite olaparib, Robson said.
“There are other broad avenues being explored,” Robson said. “One is coming in with conventional chemotherapy agents, which is hard to do because of overlapping bone marrow toxicities. Another is to combine olaparib with other targeted agents that interact with components of the DNA damage repair pathway.” – by Chuck Gormley
R eference:
Robson ME, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: AstraZeneca funded this study. Robson reports consultant or advisory roles with AstraZeneca and McKesson; travel expenses from AstraZeneca; honoraria from AstraZeneca; and research finding from AbbVie, AstraZeneca, Biomarin, Medivation and Myriad Genetics. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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This is really a major step forward. In breast cancer, we have been doing precision medicine for 120 years now, first against the estrogen receptor and second against HER-2. For patients whose cancer are negative for those two things, we have had chemotherapy, which is not very precise. This is one area we really had to work hard on. The concept of PARP and DNA repair has been around for 20 years, but it took some really smart people to put one and one together, and now we have PARP inhibitors.
There are a few issues that need to be emphasized. These patients all had germline inherited BRCA1 or BRCA2 mutations, so this is not for the general [breast cancer] population yet. Its almost as much a proof of principle as it is practice changing. These drugs do work in breast cancer if were smart and if were precise. This is a drug that has fewer side effects and works better than what we have done in the past. Thats what were trying to do for our patients: make them feel better and, hopefully, make them live longer.
The first question we have in our field is: Instead of comparing this to chemotherapy, what if we add these to chemotherapy? There are trials going on now looking at this. The second question is: Instead of waiting until patients are relatively far down the road three-quarters of these patients had already received chemotherapy in the metastatic setting what if we moved this earlier into the metastatic setting or even more exciting, perhaps into the adjuvant setting? I believe you will see trials like that conducted in the next year or two.
Finally, there are two major issues we all are concerned about, although probably not in this group of patients. One is long-term toxicities. These drugs inhibit DNA repair and, in theory, inhibiting DNA repair could be quite dangerous because we like to have DNA get repaired when it makes mistakes. Were trying to inhibit DNA in the cancer cells, but it may do that in normal cells, too, and there have been a few cases of secondary leukemias in the ovarian setting. We have to be cognizant of that. We also need to understand what the mechanisms of resistance to these drugs are. Even when they worked, the curves still ultimately came back together again. It gets back to using them in different ways, in clever ways, perhaps combining them with other sources of therapies.
Perspective
Back to TopThis is an incredibly exciting study, as it is the first randomized phase 3 trial to show a benefit for the PARP inhibitor olaparib (Lynparza, AstraZeneca) in BRCAassociated HER-2negative metastatic breast cancer compared with standard chemotherapy. BRCAassociated breast cancer cells have difficulty repairing DNA damage. PARP inhibitors, which are biologic or targeted agents, attack another way of repairing DNA damage, making these cancers particularly vulnerable to PARP inhibitors. In this trial, the response rate to the PARP inhibitor was double that of standard chemotherapy, and the chance of progression was decreased by 42% at a median follow up of 14 months. Because olaparib is a targeted agent, there were fewer side effects and better quality of life among the women randomly assigned to receive the PARP inhibitor compared with standard chemotherapy.
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This is a really interesting study. Im excited that the HR is 0.58 for olaparib (Lynparza, AstraZeneca) versus physicians choice of chemotherapy. This drug also is very well tolerated. However, Im a little disappointed that PFS was 7 months vs. 4.2 months. I think a lot of us would have expected longer. Subset analyses are being done that may provide more detail.
Nonetheless, PFS is almost doubled and that is important. We dont have agents that have efficacy in triple-negative breast cancer other than chemotherapy. The trial I would most like to in triple-negative, BRCApositive breast cancer is for everyone to receive chemotherapy, and then receive either olaparib or placebo. Im sure there are lot of designs under consideration, but we are excited about this and well see what happens. In triple-negative breast cancer, OS will be the million-dollar question. If there is an OS benefit, this will be a home run. Right now, its a double.
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OlympiAD is a great proof-of-principle trial for the use of PARP inhibitors in hereditary breast cancer. Olaparib (Lynparza, AstraZeneca) showed it was better than chemotherapy in terms of effectiveness and it also was less toxic, so it is a very nice option. There has been a decades worth of research building toward approval for these drugs in BRCAassociated breast cancer, and I think this should lead to regular use of this class of drugs in these patients.
A corollary is that we now need to test women who have metastatic breast cancer for BRCA1 or BRCA2 because, if you have a targeted therapy, you need to check to see if the target is there. That is not something we have universally done, but we will be doing more of that in the future. Hopefully this opens the door to a whole area where you start to build on PARP inhibitors, either with immunotherapy, another PARP inhibitor or another DNA repair agent. People who spend a lot of time thinking about this mechanistic pathway are very excited about that.
There have been a lot of phase 2 studies with this class of drugs. The OlympiAD data in general were very consistent with previous reports, with a response rate on the order of 30% to 40% and PFS of 6 to 8 months.
There is a question about how olaparib might stack up against platinum-based chemotherapy. OlympiAD excluded platinum as one of the investigators choice options, so it doesnt exactly solve the problem. However, I think its a concrete step forward, even if its not a giant leap forward.
Are the OS data which are not yet available really important for determining whether we would use the drug? I think the answer is no. We had patients on OlympiAD, and I have one in particular who has been on this drug for 2.5 years. She has had a complete response and truly is doing beautifully. She forgets to come in for appointments because she feels so good. Thats a big win.
There is a value discussion happening around several products now regarding whether improvements in PFS are important enough to justify coverage and the cost of these drugs. I dont have the answer for olaparib but I think thats part of the discussion.
Perspective
Back to TopThese results confirm some of the results we have seen in smaller studies. This exciting study showed that in this patient population, PARP inhibitors led to increase in PFS with lower rates of toxicities. As patients who harbor BRCA mutations have higher incidence of triple-negative breast cancer, this would offer a first targeted agent in this patient population. It certainly adds another option for our patients, but it will affect triple-negative breast cancer the most, as options in that disease are so limited.
Questions remain about an OS benefit, proper sequencing or combination of therapies, and long-term toxicities from this class of drugs. Further, we do not know whether this therapy is better in patients with metastatic disease or, possibly, in patients with curable diseases.
With multiple agents already approved in ovarian cancer, there are several studies that will provide some answers in the next few years and are eagerly anticipated. Long-term toxicities — especially the development of leukemias, which has been seen in ovarian studies — will need to be closely monitored. It will be interesting to find out if other patients with DNA repair dysfunction obtain the same benefit as germline BRCA–mutated patients. This would increase the number of patients who can potentially benefit from the therapy.
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