OncLive recently published the views of several speakers at its State of the Science Summit on breast cancer. Stephanie LaBomascus, MD gave a presentation that highlighted triple negative breast cancer (TNBC), describing it as heterogeneous, or composed of dissimilar elements. TNBC accounts for approximately 15% of all breast cancer diagnosed.
Dr. LaBomascus commented that she does not expect a “one size fits all” solution. She emphasized that a thorough knowledge of the basic difference in these tumors, as well as their biology, will lead the way to targeted therapies.
Certain elements not found in TNBC are three receptors that stimulate the growth of cancer: HER-2 gene, estrogen, and progesterone. Therefore, the fact that these receptors are not present in TNBC limits the effectiveness of treatments such as hormone therapy or drugs that generally target these receptors.
On The Horizon
Although the heterogeneous nature of TNBC makes it difficult to target, there are three therapies that offer significant promise:
- PARP inhibitors
- antibody-drug conjugates (ADCs).
Immunotherapy: Landmark phase III IMpassion130 trial.
TNBC exhibits the highest aggressive immune response (known as tumor infiltrating lymphocytes) of all other breast cancers. These lymphocytes are responsible for killing tumor cells.
Clinical trials using monotherapy (one drug) have been conducted over the years with several readily available drugs but with minimal success. As a result, researchers began studying the effect of chemotherapy combined with immunotherapy which led to the landmark phase III IMpassion130 trial (NCT02425891).
Nine hundred patients at multiple locations were enrolled in the double-blind study with investigators and participants masked as to which patients received the drug or the placebo.
Patients with previously untreated metastatic triple-negative breast cancer or inoperable locally advanced breast cancer were eligible. The endpoints were progression-free survival and overall survival.
At the end of a two year period, fifty-four percent of patients receiving the immunotherapy had survived as opposed to thirty-seven percent overall survival for the patients with the placebo. In addition, the adverse events followed the drug’s safety profile. These final results led to the FDA’s approval in accordance with the Ventana PD-L1 investigation conducted in the trial.
It is significant that this phase III trial is the first to have been approved by the FDA for immunotherapy in breast cancer.
PARP (Poly(ADP-ribose) Polymerase Inhibitors in Breast Cancer 1 and Breast Cancer 2 (BRCA1/2)
The most important function of DNA is to carry genes which are segments of DNA that are passed down from parents to children. DNA is composed of two long, twisted strands that contain genetic information.
BRCA1 is a gene that normally restrains the growth of cells in the breast but if it becomes mutated it leads to breast cancer. When genetic lesions such as BRCA1/2 disrupt double break (double-stranded) DNA repair it is often associated with cancer susceptibility.
Single stranded breaks in DNA are repaired by PARP1 which is an important mechanism in repairing DNA. Dr. LaBomascus explained that patients with BRCA1/2 mutations are susceptible to DNA double-stranded breaks but they can be repaired with PARP enzymes.
FDA Approved PARP Inhibitors
To date there are two FDA approved PARP inhibitors for BRCA patients diagnosed with germline BRCA (gBRCA) breast cancer:
- olaparib (Lynparza), and
- talazparib (Talzenna)
Olaparib Monotherapy Phase III Trial (OlympiAD)
NCT02000622 is a Phase III open label, randomised, controlled, multi-centre study to assess the efficacy and safety of olaparib monotherapy versus physicians choice chemotherapy in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations.
A total of 302 adult patients with known and unknown BRCA status were enrolled in 125 centers across 19 countries beginning in 2014. The results of the trial were last updated in December 2018. As an open label trial, the investigators and patients were aware of which patients received either olaparib, chemotherapy or a placebo. The trial was designed to compare olaparib with one of three chemotherapy agents or a placebo.
Study results showed a response rate for olaparib of 59.5% while the response rate for the placebo was 28.8%. The primary endpoint was progression free survival (PFS). Olaparib’s PFS was 7 months versus a PFS for the placebo of 4.2 months.
Both the olaparib arm and the chemotherapy arm had similar levels of tolerability with the exception of anemia in the olaparib cohort. The chemotherapy arm had a higher rate of neutropenia (a low number of cells in the immune system).
A second trial combining olaparib and platinum-based chemotherapy in patients with basal-like TNBC is currently being conducted. Approximately 70 to 90 percent of triple-negative breast cancers are basal-like. One aspect of the trial is to determine if PARP can improve upon the efficacy of platinum chemotherapy.
Dr. LaBomascus explained that the phase III PARTNER trial () is being conducted because basal-like breastNCT03150576 cancers and gBRCA have a similar biological deficiency.
The Phase III EMRACA Trial
A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA)
The EMRACA trial (NCT01945775), a study of the second approved drug talazoparib, is similar in design to the OlympiAD trial. About fifty percent of patients in the talazoparib cohort presented with TNBC but unlike the EMRACA trial, the disease had advanced in a larger proportion of patients. Most of the patients were treated previously with chemotherapy. The EMRACA study began in 2013, was last reported in March 2019, and enrolled a total of 431 patients.
The talazoparib and the placebo arms exhibited somewhat better rates of progression free survival over the OlympiAD study (8.6 months and 5.6 months). Response rates were consistent with OlympiAd.
Antibody-Drug Conjugates (ADCs)
There are several advantages to ADCs. They target the cellular tissue and provide a higher level of potency while at the same time limiting side effects. The process involves attaching cytotoxic drugs to antibodies by way of a linker protein. Then they travel to the tumor cell causing cell death.
Dr. LaBomascus described sacituzumab govitecan as one of two ADC compounds being developed. In a 2016 article, the Journal of Clinical Oncology quoted clinical trial researchers as concluding that sacituzumab govitecan was well tolerated and induced early and durable responses in patients with metastatic TNBC who had received previous treatment.
A new trial, phase III ASCENT (NCT02574455) compares the ADC with chemotherapy in patients who have either relapsed or who have not responded to previous therapies.
The second ADC referenced by Dr. LaBomascus, ladiratuzumab vedotin, exhibited an overall response rate of 37%. Studies are being conducted as monotherapy (NCT03424005) and in conjunction with immunotherapy (NCT03310957).
The recent approval of immunotherapy in breast cancer gives Dr. LaBomascus and researchers encouragement and motivation to continue their work in providing improved results for breast cancer patients.