Amy Karon, MPH

Germline mutations of BRCA 1/2 affect about 5% of patients with breast cancer and are associated with triple-negative breast cancer (TNBC), which has a poor prognosis and has been notoriously resistant to targeted therapies.

After more than a decade of development, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may offer these subgroups of patients an option &ldquo;that appears to be better in many ways than conventional chemotherapy,&rdquo; said Mark E. Robson, MD, a medical oncologist and clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center.

Robson was lead investigator of the open-label phase III OLYMPIAD trial (NCT02000622) in which olaparib (Lynparza), an oral PARP inhibitor, was associated with a nearly 3-month improvement in median progression-free survival (PFS) compared with physician&rsquo;s choice of conventional single-agent chemotherapy in patients with heavily pretreated HER2-negative metastatic breast cancer and a confirmed or suspected germline BRCA mutation.

The median PFS was 7 months in the olaparib (300 mg twice daily) group and 4.2 months in the group that received 21-day cycles of either capecitabine (Xeloda), eribulin (Halaven), or vinorelbine (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P <.001), Robson and his associates reported at the 2017 ASCO Annual Meeting.

The difference in this primary endpoint was slightly more striking among patients with TNBC (HR, 0.43; 95% CI, 0.29-0.63).

&ldquo;Inclusion of patients with TNBC in this study is important, given the limited treatment options for these patients after anthracyclines and taxanes,&rdquo; the investigators wrote when the findings were published simultaneously in the New England Journal of Medicine.

OLYMPIAD is the first of several phase III breast cancer trials of PARP inhibitors that &ldquo;hopefully will lead to FDA approvals and will be a promising option for women with BRCA mutations,&rdquo; Robson said. &ldquo;The question is whether we can improve the effectiveness of treatment in these women as well as in other populations of women with breast cancer, either through better selections or through biomarker analyses.&rdquo;

Results from OLYMPIAD cap more than a decade of work on PARP inhibition in ovarian, breast, and other cancers. Although the PARP enzyme family is involved in many cellular functions,

PARP-1 is the most abundant and best characterized for its vital role in repairing single-strand DNA breaks.

Based on this premise, investigators first developed PARP inhibitors to boost the cytotoxicity of chemotherapy and radiation.

By 2005, researchers found that BRCA 1/2-mutated cells from humans and mice were profoundly sensitive to PARP inhibitors, which triggered chromosomal instability, cell cycle arrest, and apoptosis.

These in vitro findings made sense, considering that the BRCA1 and BRCA2 proteins facilitate double-stranded DNA repair through the homologous recombination pathway, experts noted.

Deleterious BRCA mutations render cells deficient in BRCA proteins and are therefore unable to efficiently activate the homologous recombination apparatus. As a result, they rely on secondary PARP-dependent pathways to repair DNA damage.

By trapping PARP at the site of DNA damage repair, PARP inhibitors stall DNA replication and repair, ultimately leading to cytotoxic double-strand breaks in BRCA-deficient cells.

Inhibitors of PARP were first developed to treat BRCA-associated ovarian cancers, and work progressed rapidly in this setting.

By 2013, multiple phase III studies were enrolling patients, and by 2014, the FDA had approved olaparib as a third-line monotherapy for women with advanced ovarian cancer with confirmed or suspected germline BRCA mutations. Rucaparib (Rubraca) received a similar approval for ovarian cancer in 2016, and in 2017, the FDA approved both niraparib (Zejula) and olaparib oral tablets as maintenance therapies for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who had a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.

Olaparib tablets were also approved for the treatment of adult patients with deleterious or suspected germline BRCA-mutated advanced ovarian cancer who have received &ge;3 prior chemotherapy regimens.

BRCA mutations also play an important role in breast cancer, but trials in this setting have been slower to demonstrate the efficacy of PARP inhibition. Consider iniparib, the now-defunct investigational agent that showed promise in a phase II trial of patients with TNBC, but flopped in 3 phase III trials of patients with breast, ovarian, and squamous nonsmall cell lung cancers.

Experts concluded that iniparib did not strongly inhibit PARP and that the crossover design of the phase II trial might have biased the results toward the agent.

Aside from iniparib, the development of PARP inhibitors has been more difficult in breast cancer than in ovarian cancer, said Robson. He explained that most ovarian cancer trials of PARP inhibitors focused on maintenance therapy or enrolled women who had previously responded to a particular platinum-based chemotherapy treatment, which predicts response to PARP inhibition. &ldquo;In breast cancer, we don&rsquo;t usually treat that way,&rdquo; he said. &ldquo;Platinum has not been a commonly used agent, although that is changing. And in the United States, at least, the treatment of breast cancer tends to be ongoing until you move on to the next therapy.&rdquo;

Because the paradigm of maintenance therapy was uncommon in breast cancer, researchers had to compare PARP inhibitors head-to-head with chemotherapy, spurring extensive discussions about how best to do so, according to Robson. Breast cancer also might be more heterogeneous than ovarian cancer, he said. &ldquo;For example, in OLYMPIAD, half of patients were triple-negative and half were HER2-positive.&rdquo;

These challenges made OLYMPIAD&rsquo;s results noteworthy. Olaparib not only met the primary endpoint of PFS, but produced a higher response rate than chemotherapy (59.9% vs 28.8%) with a 36.6% risk of grade 3 or worse adverse events (AEs) compared with a 50.5% rate for chemotherapy.

The trial did not find a difference in overall survival (OS) between the groups, but it was not powered to do so. Moreover, patients in the chemotherapy group were more likely to receive PARP inhibitors, platinum-based treatment, or cytotoxic chemotherapy after disease progression, which could also confound analyses of this endpoint, the investigators noted.

Compared with chemotherapy, olaparib was also associated with a 7.5-point relative improvement (P = .004) in quality of life as measured by the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.

&ldquo;Our formal definition of deterioration of quality of life was a 10-point drop in that instrument, and this was significantly delayed in people who received olaparib,&rdquo; Robson said. &ldquo;Olaparib was associated with fatigue, nausea, and anemia, but these were usually mild and did not lead to treatment discontinuation, whereas individuals who had chemotherapy had low blood cell counts and also developed hand-foot syndrome, or palmar-plantar erythrodysesthesia.&rdquo;

&ldquo;We see an improvement in PFS,&rdquo; said Robson of OLYMPIAD&rsquo;s major takeaways. &ldquo;Whether there&rsquo;s also an improvement in OS remains to be seen, but it did appear that the therapy was less toxic in several ways than conventional chemotherapy and women&rsquo;s quality of life was preserved for a longer period.&rdquo;&nbsp;

Many more trials are underway that should help address remaining questions about PARP inhibitors in breast cancer, Robson said. Ongoing studies are comparing conventional chemotherapy versus combination therapy with PARP inhibitors plus other agents that target DNA damage repair pathways (TABLE).

Moving forward, additional studies are assessing olaparib as maintenance therapy after platinum-based treatment of breast cancer and are also studying PARP inhibitors in combination with immune checkpoint inhibitors.

For the time being, OLYMPIAD provides the most promising data on PARP inhibitors in breast cancer, said Allison W. Kurian, MD, MSc, a medical oncologist and associate professor of oncology and health research and policy at Stanford University Medical Center. Among phase III trials of PARP inhibitors in breast cancer with readouts to date, only OLYMPIAD has met its primary endpoint.

The oral investigational PARP inhibitor veliparib (ABT-888) fell flat in a phase III placebo-controlled trial (NCT02032277) of patients receiving standard neoadjuvant therapy for early-stage TNBC, investigators reported at the 2017 ASCO Annual Meeting. Adding veliparib to carboplatin and paclitaxel did not significantly improve the rate of pathological complete response (53.2% vs 57.5% with placebo; P = .36).

Veliparib also did not significantly improve median PFS when added to paclitaxel and carboplatin in the placebo-controlled phase II BROCADE trial (14.1 vs 12.3 months with placebo; HR, 0.79; 95% CI, 0.54-1.16; P = .231).

Results from the phase III sister trial (BROCADE-3; NCT02163694) in patients with HER2-negative metastatic or locally advanced unresectable BRCA-associated breast cancer are expected in 2018.

Kurian is especially &ldquo;eager to see results of the phase III EMBRACA trial, which is investigating the PARP inhibitor talazoparib in BRCA 1/2 mutation carriers with metastatic breast cancer,&rdquo; she said. EMBRACA (NCT01945775) uses the same study design as OLYMPIAD, comparing the oral investigational PARP inhibitor with physician&rsquo;s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

&ldquo;Using the same design as OLYMPIAD will be useful because it hopefully will confirm the results of OLYMPIAD with a different drug,&rdquo; said Robson. The trial also has enrolled more patients than OLYMPIAD, which might better power it to detect a difference in OS, he added.

The associated phase II trial (ABRAZO; NCT02034916) evaluated talazoparib (1 mg/day; 21-day cycles) in 70 patients with locally advanced or metastatic breast cancer with BRCA mutations who either had responded to platinum-based treatment or had received at least 2 prior lines of nonplatinum chemotherapy. The objective response rate was 24% in patients with BRCA1 mutations, 34% in patients with BRCA2 mutations, 26% in women with TNBC, and 29% in women with HER2-positive disease.

As with olaparib, the most common AEs included anemia (52%), fatigue (45%), and nausea (42%).

Robson and Kurian are both anticipating the results of the phase III placebo-controlled OlympiA trial (NCT02032823), which is evaluating olaparib as adjuvant therapy for patients with early-stage germline BRCA 1/2-mutated HER2-negative breast cancer. Study investigators are still enrolling participants and intend to finish collecting data on the primary endpoint of invasive disease-free survival by 2020. Meanwhile, the phase II/ III PARTNER (NCT03150576) trial is evaluating whether adding olaparib to platinum-based therapy in the neoadjuvant setting is safe and improves the likelihood of complete pathological response at surgery in patients with TNBC or germline BRCA-mutated breast cancer.

Additionally, a phase I study determined that the combination of olaparib and cyclophosphamide was tolerable and produced antitumor activity in individuals with germline BRCA mutations and set a phase II recommended dose for the combination for further study.

Niraparib is also the subject of several studies. The phase III BRAVO trial (NCT01905592) is comparing this oral PARP inhibitor with physician&rsquo;s choice of chemotherapy in patients with HER2-negative, germline BRCA-mutated breast cancer. Earlier this year, the sponsor reported that enough patients had dropped out of the chemotherapy control arm that the trial would probably not support a registration.20 However, a phase I/II trial (NCT02657889) is recruiting patients with TNBC or ovarian cancer to study treatment with niraparib plus the antiPD-1 antibody pembrolizumab (Keytruda). Additional trials of niraparib in breast cancer are planned, but are not yet recruiting.&nbsp;

Work also continues on rucaparib, which is currently approved for the treatment of ovarian cancer in patients with somatic or germline BRCA mutations. The phase II RUBY trial (NCT02505048) is evaluating rucaparib monotherapy (600 mg twice daily in 21-day cycles) in patients with HER2-negative breast cancer and mutations of BRCA 1/2 or other genes involved in the homologous recombination repair pathway.

Topline results are expected in December 2017.

For now, it&rsquo;s too soon to say which PARP inhibitors or combinations will provide the most benefit in breast cancer, or in which patient subgroups, Robson said. &ldquo;Even in ovarian cancer, this is not clear, and it would be difficult to extrapolate from ovarian cancer to breast cancer anyway. There are material differences between the drugs, and I&rsquo;m not sure there&rsquo;s a winner to pick in terms of the best agent.&rdquo;

He emphasized that increasing numbers of patients with breast cancer are being found to have either germline or somatic BRCA mutations or mutations in other genes in the homologous recombination pathway. For example, in a recent study of 560 patients with breast cancer, investigators identified all possible mutations and developed a weighted computer model called HRDetect that detected &ldquo;mutational signatures&rdquo;somatic substitutions and patterns of DNA insertions, deletions, and rearrangement corresponding with BRCA 1/2 mutations.

Only 22 patients (4%) in the cohort had known germline BRCA 1/2 mutations, which echoes the prevalence in other studies. Strikingly, HRDetect identified 22 additional tumors with somatic BRCA mutations and 47 tumors with a functional BRCA1/BRCA2 deficiency. None of these patients had detectible BRCA germline mutations. The researchers validated HRDetect in separate groups of patients with breast, ovarian, and pancreatic cancers, where it again detected tumors with &ldquo;BRCAness&rdquo; in patients who lacked the classic germline mutations.

Testing for these mutational signatures could help physicians identify patients whose breast cancer might be sensitive to PARP inhibition even though they lack BRCA 1/2 germline mutations, the researchers concluded. Editors of the September 2017 issue of Cancer agreed, noting that up to 20% of breast cancers might be treatable with PARP inhibitors if these findings hold up in other studies.

Kurian looks even further ahead. Five to 10 years from now, she hopes that additional trials will have spurred FDA approvals of PARP inhibitors that effectively treat BRCA 1/2-associated breast cancer, both in the metastatic and early-stage, curable settings, she said. &ldquo;I also hope that we will see efficacy of PARP inhibitors among patients whose breast cancers are the result of DNA repair gene mutations other than BRCA 1/2, such as ATM [ataxia telangiectasia mutated], for which we now routinely test in clinical practice.&rdquo;

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Mark E. Robson, MD, discusses the progress that has been seen in breast cancer care with the use of PARP inhibitors.

Amy Karon, MPH | Authors

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