By: Ellie Leick
The use of PARP inhibitors has greatly expanded in the treatment of patients with BRCA-mutated breast cancer in recent years, according to Melinda L. Telli, MD, and research efforts are now examining these agents in novel combinations and beyond the BRCA setting.
In January 2018, olaparib (Lynparza) joined the treatment arsenal for use as a monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. Later that year, in October, talazoparib (Talzenna) also received regulatory approval for use in this patient population. Since then, these agents have been examined in novel combinations, according to Telli.
For example, the phase III BROCADE 3 trial randomized patients with HER2-negative, advanced or metastatic, BRCA-mutated breast cancer to receive chemotherapy comprised of carboplatin and paclitaxel in combination with either the PARP inhibitor veliparib or placebo.
Results showed that the median progression-free survival (PFS) per investigator assessment was 14.5 months in the veliparib arm compared with 12.6 months in the placebo arm (HR 0.71; 95% CI, 0.57–0.88; P = .002).1 The median PFS per independent review was even longer, at 19.3 months in the veliparib arm versus 13.5 months in the placebo arm (HR 0.70; 95% CI, 0.54-0.90). The PFS rate at 3 years was doubled with veliparib compared with placebo at 26% versus 11%, respectively. Furthermore, the median overall survival also favored the veliparib arm, at 33.5 months compared with 28.2 months in the placebo arm (HR 0.95; 95% CI, 0.73-1.2; P = .67).
“There is something about this combination and giving that up-front chemotherapy with platinum and a taxane that seems to be delaying this emergence of resistance,” said Telli. “They are really interesting data that made us ask a lot of questions in terms of how best to use PARP inhibitors in our patients with germline BRCA mutations in advanced breast cancer.”
Beyond PARP combinations, research is also starting to evaluate the efficacy of PARP inhibition beyond patients with BRCA mutations. For example, a phase II trial is examining whether additional subgroups of patients with advanced HER2-negative breast cancer or other solid tumors with germline or somatic alterations in homologous recombination (HR) pathway genes beyond BRCA can derive benefit from PARP inhibitor monotherapy. Of 12 patients evaluable for response, 3 achieved a RECIST response with an overall response rate of 25%; 2 of these patients had germline PALB2 mutations and 1 had germline CHEK2/germline FANCA/somatic PTEN mutations.2
In an interview with OncLive, Telli, an associate professor of medicine in the Division of Medical Oncology at Stanford University School of Medicine, director of the Breast Cancer Program at the Stanford Cancer Institute, and associate director of the Stanford Women’s Cancer Center, discussed the role of PARP inhibition in the treatment of patients with breast cancer who harbor the BRCA mutations and ongoing research efforts seeking to expand their use beyond this setting.
OncLive: What are the clinical indications of PARP inhibitors and other targets?
Telli: Recent data have examined PARP inhibitors as treatment for patients with germline mutations in BRCA1/2 with advanced breast cancer. There are also data that have evaluated the use of these inhibitors beyond those with BRCA mutations; with that research, investigators seek to determine what the potential application is there. Finally, some new drugs are targeting DNA repair defects in breast cancer and we’re starting to see some early data reported.
With regard to PARP inhibitors in advanced breast cancer, 2018 was a really important year. We saw the approval of the first 2 PARP inhibitors, olaparib and talazoparib, for the treatment of patients with advanced breast cancer and BRCA1/2 germline mutations. These inhibitors were approved as monotherapies based on results from 2 large phase III trials that demonstrated that PARP inhibitor monotherapy improved progression-free survival (PFS) in this group of patients compared with single-agent chemotherapy.
Importantly, in the comparison with chemotherapy, [the investigators] didn’t look at DNA-damaging chemotherapeutics as the comparison, so no platinum was included. However, we did manage to get these drugs into the clinic and we’ve been able to [make them] accessible for patients, which has been really important. One of the big challenges that we face in the clinic is that we see patients initially respond to these inhibitors, sometimes rapidly, but then they develop resistance after a period of treatment. When resistance develops, what should we do?
We have recent data from a very important phase III clinical trial in this space for germline BRCA mutation carriers with advanced breast cancer called BROCADE 3; this trial was a bit different than the first 2 [trials that we conducted.] In this trial, investigators examined the PARP inhibitor veliparib or placebo, but the inhibitor was not given as monotherapy; it was given in combination with chemotherapy. Patients in the first- through third-line setting with advanced disease and a germline BRCA mutation were eligible to receive carboplatin and weekly paclitaxel, with veliparib given for 7 days of the cycle versus placebo. In the trial, patients were treated until disease progression. If patients didn’t progress, but the chemotherapy was discontinued for whatever reason, they were allowed to continue on blinded monotherapy at a higher dose.
What is important about this trial and made me think a lot about our overall strategy is that the PFS benefit that we saw in absolute terms was quite a bit longer than what we saw with the PARP inhibitor monotherapy studies. In that trial, the median PFS was 14.5 months with the veliparib and chemotherapy compared with 12.6 months with chemotherapy alone. However, all the action was really beyond the median. When you look at the shape of those curves for PFS, there was a significant group of patients who remained progression free 2 to 3 years out. At the 2-year mark, more than one-third of patients were progression free. At the 3-year mark, more than a quarter [of patients] were progression free.[As such, these results] are quite different from what was observed in the other studies, where the PFS was more on the order of 7 to 8.5 months. The overall strategy was more like a strategy that one might use in ovarian cancer, which hasn’t been the approach we’ve taken in breast cancer thus far. In ovarian cancer, patients receive induction chemotherapy in combination [with a PARP inhibitor], and then maintenance with a PARP inhibitor. The data from BROCADE 3 really makes us question whether we should be considering the use of that type of a strategy in our patients [with breast cancer].
What are some unanswered questions left by BROCADE 3?
The big issue with BROCADE 3 is, if I have a new patient with recurrence of breast cancer, either TNBC or estrogen receptor–positive HER2-negative [breast cancer] with a BRCA mutation, the big question is, should I move toward the strategy of PARP inhibitor monotherapy, or should I be thinking about an initial period of induction chemotherapy followed by PARP inhibitor maintenance? When I thought about this issue and how I would talk with my patients about it, it’s important to share the data from BROCADE 3. At least in that study, the approach does appear to be providing patients with much more durable PFS and overall survival; these benefits are nearly 1 year longer than what was reported in the prior monotherapy trials.
What research is being done with PARP inhibitors beyond BRCA1/2 mutations?
There is a lot of interest in examining PARP inhibitor applications beyond germline BRCA1/2 mutations in breast and other cancers. Some small studies have been done in breast cancer. We presented data earlier this year from our talazoparib beyond-BRCA trial, which definitely showed a signal for talazoparib monotherapy activity in patients with germline PALB2 mutations. Some other studies are ongoing with olaparib. This is an area where we’re seeing signals indicating that there is a role for PARP inhibitors beyond those with germline BRCA1/2 mutations.
The next big thing is investigating beyond PARP inhibitors. What are some other targets for patients with DNA damage response–¬defective tumors? A lot of interesting data are looking at a new class of drugs, such as ATR inhibitors and other DNA damage response cell cycle checkpoint inhibitors. These agents are showing some interesting early activity in patients with triple-negative breast cancer (TNBC) who lack a BRCA mutation as well as patients with ATM mutations or ATM loss in the tumor and other DNA-repair deficiencies.
Interestingly, some early-phase data from a new agent G-quadruplex stabilizer, which is from a Canadian group. That has entered the clinic and phase I data were presented recently. As we look ahead, many new targets exist beyond PARP inhibitors. In the future, we’ll learn more about how to optimize the use of PARP inhibitors in our patients with BRCA mutations, and then hopefully find a role for PARP inhibitors beyond BRCA.
What is the biggest challenge currently faced in this space?
At this point in time, the big challenge is when patients develop resistance to a PARP inhibitor. Often, they are cross resistant to other DNA-damaging therapeutics, like platinum. What do we do for those patients? This is where some of the combinations, the novel agents, and the ATR inhibitors in combination potentially with PARP inhibitors or other therapies, could have a role. We can use them to help reverse PARP inhibitor resistance.
- Diéras VC, Han HS, Kaufman B, et al. Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-assocaited breast cancer. Ann Oncol. 2019;30 (suppl 5):v857-v858. doi: 10.1093/annonc/mdz394.008
- Gruber JJ, Afghani A, Hatton A, et al. Talazoparib beyond BRCA: a phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes. J Clin Oncol. 2019;37(suppl 15, abstr 3006). doi: 10.1200/JCO.2019.37.15_suppl.3006
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.