CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 27, 2023
Expiration: March 26, 2024
Charles E. Geyer, Jr., MD:
The development of the PARP inhibitors has been interesting because the initial hope was that coadministration of PARP inhibitors with DNA-damaging chemotherapy would enhance the efficacy of chemotherapy, which would have had wide applicability. However, overlapping toxicities made that approach problematic. Although efforts to develop PARP inhibitors in combination with chemotherapy continued, the BRCA research community demonstrated that breast cancer cells with homozygous biallelic loss of either BRCA1 or BRCA2 were highly sensitive to single-agent PARP inhibition through the process of synthetic lethality.
Breast cancers that develop in patients with pathogenic variants in germline BRCA1 or BRCA2 have deficiency in homologous recombination repair (HRD), a critical, high-fidelity DNA repair pathway. To remain viable, cancer cells must maintain some ability to repair DNA, so they become dependent on an alternative repair pathway in which PARP has a central role. If PARP is inhibited in these HRD-positive cells, the worsening genomic instability induces apoptosis.9 After initial phase II studies confirmed the activity of the PARP inhibitor olaparib in patients with pathogenic variants in BRCA1 or BRCA2 and metastatic breast cancer, phase III trials in metastatic disease were initiated comparing monotherapy with a PARP inhibitor with single-agent chemotherapy (olaparib in OlympiAD in 2014 and talazoparib in EMBRACA in 2013). Positive results of these trials were published and led to the approval of both PARP inhibitors as single agents in patients with metastatic breast cancer and pathogenic variants in germline BRCA1 or BRCA2.10-13
Typically, phase III trials in early breast cancer are not initiated until positive results are observed in the metastatic setting. However, a decision was made in 2012 to evaluate adjuvant olaparib in the early breast cancer setting in the global, double-blind, placebo controlled phase III OlympiA trial in patients with germline pathogenic variants in BRCA1 or BRCA2, presenting with high‑risk TNBC.14 OlympiA was initially designed to compare single-agent olaparib vs placebo as adjuvant therapy in patients with newly diagnosed TNBC and high risk for recurrence who had completed standard treatments.
Charles E. Geyer, Jr., MD:
For the first 18 months following activation, only patients with high-risk, early-stage TNBC and pathogenic variants in germline BRCA1 or BRCA2 were enrolled. A concern with limiting the trial to patients with TNBC was that although the majority of individuals with germline pathogenic variants in BRCA1 develop TNBC, we see the opposite with BRCA2, where patients are more likely to be ER positive. In addition, tumors with low-intensity ER staining are often of the basal or luminal B subtype when assessed for intrinsic subtype, and derive less benefit from adjuvant endocrine therapies.15 There was also growing recognition that OlympiA provided the only opportunity to assess the activity of PARP inhibition in patients with pathogenic variants in germline BRCA who developed ER‑positive/HER2‑negative disease. After pharmacokinetic studies demonstrated that there were no interactions with endocrine therapy, OlympiA was amended to include patients with high-risk, HR-positive/HER2-negative breast cancer.14
The eligibility criteria for patients with HR‑positive disease are unusual in contrast to the straightforward TNBC criteria: TNBC without a pCR following neoadjuvant chemotherapy or if treated with initial surgery, positive lymph nodes or at least a T2 tumor with negative nodes. An important safety concern regarding use of adjuvant olaparib in the curative intent setting was the potential of leukemogenic effects of the therapy, hence the initial decision to only enroll patients with high-risk TNBC. The decision to enroll patients with HR-positive disease in this context meant it was necessary to identify patients with similar risks for recurrence as in the triple-negative cohort. Thus, patients with HR-positive disease with initial surgery were required to have ≥4 positive lymph nodes to be eligible.
Patients with HR-positive disease who had received neoadjuvant chemotherapy proved more challenging to identify: The eligibility criteria for this group employed the CPS+EG clinical score, developed at MD Anderson Cancer Center as a method of quantifying residual risk in patients treated with neoadjuvant chemotherapy. The scoring system combines pretreatment clinical stage, final pathologic stage, ER status, and nuclear grade. Patients with HR-positive/HER2-negative breast cancer were required to have a CPS+EG score of ≥3 to be eligible. Although it is a simple and straightforward score, it is not used routinely, so many physicians may not be familiar with this tool.
Charles E. Geyer, Jr., MD:
The trial was activated in June 2014 and finished accrual in May of 2019 with 1836 patients.14 The study accrued a young patient population with a median age of 42 years (interquartile range: 36‑49). A little more than 70% of patients had BRCA1 pathogenic variants. Not surprising, three quarters of patients chose mastectomy, given their underlying germline pathogenic variants. Approximately 80% had TNBC, and approximately 60% were premenopausal. Approximately one half received adjuvant and one half received neoadjuvant chemotherapy. Although the decision was made to not mandate concurrent administration of olaparib or placebo with endocrine therapy in patients with HR-positive breast cancer, it was recommended and 87% of the patients receiving olaparib received concurrent endocrine therapy.
Charles E. Geyer, Jr., MD:
OlympiA was designed to detect a 30% reduction (hazard ratio: 0.70) in invasive disease‑free survival (iDFS) events but included a planned interim analysis to detect if the therapy was more effective.14 At ASCO 2021, Tutt and colleagues reported results of the interim analysis which demonstrated a hazard ratio of 0.58, corresponding to a 42% reduction in iDFS events with olaparib vs placebo (P <.001); this resulted in an absolute 3‑year improvement in iDFS of nearly 9%.14,16
Since the majority of these patients had TNBC, it was not surprising that most of the iDFS events were distant recurrence. Although the other events that contribute to the composite iDFS endpoint—locoregional recurrences, contralateral breast cancers, second malignancies—are important in a patient population with germline pathogenic variants, the bulk of the events observed were distant disease. The study was designed to proceed with formal evaluation of distant disease‑free survival (DDFS) if iDFS met statistical significance, and results showed the hazard ratio was virtually the same at 0.57, with an absolute reduction in distant disease events at 3 years of 7.1%.
OS results demonstrated 86 deaths on the placebo arm and 59 on the olaparib arm. This represented a hazard ratio of 0.68, but since this was an early analysis, it did not meet the prespecified significance boundaries.
In this interim analysis, there was no evidence of increased rates of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), with 2 cases reported in the olaparib arm and 3 in the placebo arm. However, given the short follow-up of 2.5 years, further follow-up was needed.
At the planned second interim analysis for OS, statistically significant improvement in OS was demonstrated in the intention-to-treat population.17,18 The hazard ratio was the same as it had been previously—0.68—but the 39 additional deaths that had been reported gave sufficient power to formally declare that significant improvement in OS had been shown. The improvement amounted to an absolute of 3.4% at 4 years.
Charles E. Geyer, Jr., MD:
The second interim analysis of OS also allowed for updating results for iDFS and dDFS.18 With the additional year of follow-up, the benefit with olaparib continued without any change. Based on the results of the OlympiA trial, adjuvant olaparib was approved by the FDA in March 2022 for patients with high-risk HER2-negative early breast cancer and deleterious or suspected deleterious germline BRCA mutations who had received (neo)adjuvant chemotherapy.12
Charles E. Geyer, Jr., MD:
The adverse events were as expected from what had been observed in the metastatic setting. Nausea was the most common toxicity.17 Fatigue is a recognized toxicity with olaparib in the metastatic setting and is often present in patients after completion of rigorous standard treatments for early breast cancer. In OlympiA, 27% of patients receiving placebo reported fatigue compared with 40% receiving olaparib. Anemia was present in 24.0% of patients receiving olaparib, with 9.0% having grade 3 anemia and 5.8% requiring red blood cell transfusion support.18
Charles E. Geyer, Jr., MD:
Additional good news with the second interim analysis was that there were no new cases of MDS or AML reported during the additional year of follow-up.18
Charles E. Geyer, Jr., MD:
Finally, it was important to note that when evaluating the data collected on the quality-of-life instruments, there were only minimal differences between the placebo and the olaparib arms, which is reassuring.19
Banu Arun, MD:
Knowing that we have this significant benefit with a targeted agent in the adjuvant setting for early breast cancer, which patients should be treated? How can we identify them? We have the NCCN guidelines that identify which patients to test for BRCA1/2, including everyone with breast cancer aged 50 years or younger, or anyone at any age if therapeutic implications are present.20 For metastatic breast cancer, that would include all patients. In the adjuvant setting, it would include those who fulfill the criteria that Dr. Geyer mentioned based on the OlympiA trial: TNBC with no pCR after neoadjuvant chemotherapy, node positive or tumor size ≥T2 with receipt of previous adjuvant therapy; patients with HR-positive/HER2-negative breast cancer who did not achieve a pCR after neoadjuvant chemotherapy and have a CPS+EG score of ≥3; and patients with HR-positive/HER2-negative disease with ≥4 positive lymph nodes and receipt of previous adjuvant chemotherapy.
Again, it is important to have correct pathology information available. The guidelines also mention some other factors. Ms Shannon, as a genetic counselor, what are your thoughts?
Kristen Shannon, MS, CGC:
Individuals with breast cancer at any age where a PARP inhibitor is a treatment option should be tested. That includes anyone with metastatic disease in addition to those meeting the OlympiA trial criteria.20-22 Also, in terms of the pathology and histology, other patients who should receive BRCA testing include those with triple‑negative tumors, multiple primary breast cancers, lobular breast cancer with a personal or family history of diffuse gastric cancer (which doesn’t really speak to BRCA1/2), male breast cancer, or Ashkenazi Jewish ancestry. Also, patients should be tested for BRCA mutations if there is a personal history at any age with ≥1 close relative with breast cancer at 50 years of age or younger, ovarian cancer, pancreatic cancer, prostate cancer, or ≥3 total diagnoses in the family or ≥2 other close relatives with breast cancer.
As you can see, this leads to many patients with breast cancer who should consider testing. It is important to note that another guideline exists from the American Society of Breast Surgeons that recommends anyone with breast cancer should undergo BRCA testing.23 At this time, most (if not all) patients with breast cancer should consider BRCA1/2 testing according to agreed-upon guidelines.
Charles E. Geyer, Jr., MD:
Do you mean BRCA testing at diagnosis in the early-stage setting? The metastatic setting is somewhat complicated because we’re doing more testing with somatic next-generation sequencing; if somatic testing shows mutations in BRCA1/2, reflex germline testing follows. The challenging question in early breast cancer has become: When do you do BRCA testing in a patient with ER‑positive disease? Although there is currently broad application in the triple‑negative population, I think the real challenge is when to test patients with ER-positive breast cancer in the absence of onset at an early age or of strong family history suggestive of hereditary breast cancer.
Kristen Shannon, MS, CGC:
I think it depends on your facility and what your goal is. If the goal is to test every single patient with breast cancer at some point in the course of their treatment, it might make sense to complete the testing at the time of diagnosis as part of the initial workup to make it routine. That way the information exists if there is a need for it in the future. For example, a patient may be diagnosed and be disease free for many years and then recur with metastatic disease. If the testing had been performed at the time of diagnosis, decisions regarding treatment of the metastatic disease can be made more efficiently.
In addition to the breast cancer therapeutic implications, it is important to remember that BRCA1/2 status has implications for the patient in terms of risk for other cancer(s) and provides crucial information for family members. A woman with breast cancer and a BRCA1 pathogenic variant, for example, should be aware of the significant risk of ovarian cancer and the need for risk-reducing bilateral salpingo-oophorectomy (RRBSO). She also could provide this information to her relatives so that they may benefit from it.
Consider the case above of a woman diagnosed with breast cancer who is disease free for many years. If she has a BRCA1 pathogenic variant, testing her at the time of diagnosis would provide information on her ovarian cancer risk that would be immediately helpful to her care and she would have a RRBSO. If she didn’t undergo testing at that time and was lost to follow-up or thought to be cured of her breast cancer, she may very well develop ovarian cancer in the time before she recurred and was a candidate for BRCA testing. This ovarian cancer could have been prevented if she had been tested at the outset of her disease.
It is important to point out, however, that genetic testing (whenever it is offered) should be provided along with genetic counseling so that the patient truly understands the implications of the test and the results.
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