Broader Applications for Targeted Agents in Breast Cancer Expand Patient Use

Joshua J. Gruber, MD

Joshua J. Gruber, MD

A greater understanding of the mechanisms underlying endocrine resistance, along with the development of targeted agents directed at key regulatory oncogenic pathways, continue to lead to new options in the treatment of hormone receptor (HR)—positive, HER2-negative breast cancer. These therapies offer the promise of better disease control rates and improved quality of life for patients with advanced disease.¹

HR-positive, HER2-negative breast cancer is the most common subtype, accounting for more than 70% of breast cancer cases.²Endocrine therapy  is the mainstay of first-line treatment of this disease in patients without visceral crises, yielding improved outcomes in early and metastatic disease.³However, de novo or acquired resistance to endocrine therapy remains a significant clinical challenge, leading to therapeutic failure and limiting survival, especially in patients with metastatic disease.³

Targeted agents approved or in clinical development for treatment of HR-positive, HER2-negative disease include CDK4/6 inhibitors, selective PI3K inhibitors, and PARP inhibitors. These advances have had practice-changing implications; for instance, CDK4/6 inhibitors have yielded significant improvements in progression-free survival (PFS) and are  now the treatment of choice in patients with HR- positive, HER2-negative, treatment-naïve or endocrine therapy—pretreated metastatic breast cancer without visceral crisis.¹In addition, exciting overall survival (OS) data from pivotal trials for CDK4/6 inhibitors are helping to inform the magnitude of benefit in patients with advanced ormetastatic disease.^4-6

“The value of having these different inhibitors on the market is in  the ability to tailor [treatment] to a specific patient who may have certain comorbidities and be able to give them the appropriate therapy,” said Joshua J. Gruber, MD, an instructor of medicine in the division of medical oncology at Stanford University Medical Center in California.

Moreover, alpelisib (Piqray), the first FDA-approved PI3K inhibitor  for  the  treatment  of postmenopausal women, as well as men, withPIK3CA-mutated tumors, also gained the first new drug application for a new molecular entity approved under the FDA’s Real-Time Oncology Review pilot program.⁷

In Recent Updates, CDK4/6 inhibitors Show Survival Advantages

Three CDK4/6 inhibitors are approved for breast cancer. The first, palbociclib (Ibrance), received accelerated approval in 2015 for the first-line treatment  of estrogen receptor (ER)—positive, HER2-negative advanced breast cancer for postmenopausal women, in combination with letrozole, based on the phase II PALOMA-1 study.8 Later, both ribociclib (Kisqali) and abemaciclib (Verzenio) gained  similar  indications  in this patient population based on study results in MONALEESA-2^9,10and MONARCH 3,^11,12respectively. Additionally, abemaciclib is approved as monotherapy for adults who progressed following endocrine therapy and prior chemotherapy in the metastatic setting.

Ribobiclib

Results of a protocol-specified interim analysis of OS from ribociclib treatment in the MONALEESA-7 trial were recently published and showed an OS rate  at  42 months of 70.2% (95% CI, 63.5%-76.0%) in the ribociclib  group  compared  with 46.0%  (95%  CI, 32.0%-

58.9%) in the placebo group (hazard ratio,  0.71; 95% CI, 0.54-0.95; P = .00973 by log-rank test).^4,5

“Improvement in overall survival is the best endpoint one could hope for,” said Aditya Bardia, MD, MPH, one of the report’s authors, as well as an assistant professor of medicine at Harvard Medical School and an attending physician at Massachusetts General Hospital, both in Boston. “[This] highlights the impact of CDK4/6 inhibitors in changing the natural history of metastatic HR-positive breast cancer.” Results of the MONALEESA-3 trial presented at the European Society for Medical Oncology (ESMO) 2019 Congress showed that first and second-line treatment with the CDK4/6 inhibitor ribociclib plus fulvestrant significantly improved overall survival in postmenopausal patients with HR-positive, HER2-advanced breast cancer. These benefits were seen in women not previously treated with hormonal therapy as well as  in  those who had become resistant to endocrine therapy.¹³

“[CDK4/6 inhibitors] seem to improve survival by about a  year  in  patients  with  ER-positive disease,” Gruber  said.  “It  has  been  one  of the  most  important  advancements in metastatic breast cancer within the past 5 or 10 years. It has had a dramatic impact.”

Previously reported data from MONALEESA-3 showed that ribociclib induced a median PFS of 20.5 months (95% &nbsp;CI, 18.5-23.5) versus placebo at 12.8 months&nbsp; (95% CI, 10.9-16.3), resulting in a statistically significant improvement in the primary endpoint (hazard ratio, 0.593;95% CL, 0.480-0.732,P<.001).¹⁴

In a recent reversal of an earlier decision to reject ribociclib, the National Institute of Health and Care Excellence in the United Kingdom recommended ribociclib in combination with fulvestrant for use on the British&nbsp; National&nbsp; Health&nbsp; Service—where exemestane plus everolimus is the most appropriate alternative&mdash;based on the second-line subpopulation of the MONALEESA-3 trial. In this subgroup of patients who had received up to 1 line of prior endocrine therapy for advanced disease, the ribociclib combination demonstrated a&nbsp; median PFS of&nbsp; 14.6 months compared with 9.1 months for the placebo arm.^14,15

Abemaciclib

Another CDK4/6 inhibitor, abemaciclib is highly selective, reversible, and currently the most potent of the approved agents, with reported concentration of inhibitor required for achieving&nbsp; 50%&nbsp; inhibition, or IC50, of 2 nM and 10 nM for CDK4 and CDK6, respectively. The brain-blood-barrier crossing potential of abemaciclib has also generated interest in clinical evaluation in patients with ER-positive breast cancer and brain metastases.¹⁶

Assessment of abemaciclib levels from clinical samples obtained in the JPBO study—a phase II, Simon 2-stage design trial evaluating 6 patient cohorts with brain metastases secondary to HR-positive metastatic breast&nbsp; cancer,&nbsp; non—small&nbsp; cell&nbsp; lung&nbsp; cancer,&nbsp; or melanoma&mdash;showed comparable abemaciclib levels in brain metastases tissues, cerebrospinal fluid, and time-matched plasma samples from patients with brain metastases secondary to HR-positive metastatic breast cancer.¹⁷

In data presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, analyses of outcomes in part 2 of the study showed that abemaciclib monotherapy yielded a confirmed objective intracranial response rate (OIRR) of 6% in 52 evaluable&nbsp; patients.&nbsp; The intracranial clinical benefit rate, which included all responses of stable disease lasting 6 months or better, was&nbsp; 25%&nbsp; and&nbsp; the&nbsp; median PFS was 4.4 months (95% CI, 2.6-5.5). Although the study did not meet the primary endpoint of 11% OIRR, the intracranial benefit in this heavily pretreated population of patients with poor prognoses prompted the authors to conclude that further studies of abemaciclib monotherapy and combinations for controlling brain metastases in cancers, including in advanced breast cancer, are warranted.¹⁸

Also at 2019 ESMO Congress, MONARCH-2 showed statistically and clinically meaningful improvement in overall survival with the CDK4/6 inhibitor abemaciclib plus fulvestrant in pre-, and peri-as well as in postmenopausal women patients with HR-positive, HER2- advanced breast cancer resistant to hormonal therapy.¹⁹The abemaciclib-plus-fulvestrant combination was approved&nbsp; based&nbsp; on&nbsp; PFS&nbsp; data from MONARCH 2, in which the combination significantly extended PFS compared with fulvestrant alone (median, 16.4 vs 9.3 months; hazard ratio, 0.553;95% Cl, 0.449-0.681;P<.001).²⁰

&ldquo;It would be important to see the published data,&rdquo; Bardia said, when asked how this relates to the OS findings observed with ribociclib therapy. &ldquo;[Although] the CDK4/6 inhibitors are broadly similar, there are subtle differences in potency; ability to impact CDK 4, CDK 6, and other CDKs; and safety profile. The latter in particular tends to [affect] clinical decision making in the setting of similar efficacy (TABLE).^9,11&rdquo;

Findings were presented in a Presidential Symposium at the ESMO 2019 Congress.⁶

PI3K Inhibitors forPIK3CA-Mutated Disease

Activating mutations or amplifications of thePIK3CAgene that encodes p110&alpha; dysregulate PI3K&alpha; expression and are common in many cancers, including breast cancer.²¹Clinical development of PI3K inhibitors is predicated&nbsp; on the importance of PI3K/AKT signaling in tumor growth and proliferation promotion, high frequency ofPIK3CAmutations in HR-positive breast cancer, and their association with the luminal B breast cancer subtype, as well as unfavorable OS outcomes in node-positive disease.^22-24

Agents Under Investigation

The pan-PI3K inhibitor buparlisib and the PI3K-selective inhibitors taselisib and alpelisib have been tested in clinical trials,&nbsp; and&nbsp; the&nbsp; FDA recently granted an approval to alpelisib combined with fulvestrant for the treatment of postmenopausal women, as well as men, withPIK3CA-mutated tumors.⁷This marks the entry of the first PI3K inhibitor into the breast cancer therapeutic landscape.

Taselib

The potent and selective PI3K inhibitor taselisib (GDC-0032) has demonstrated&nbsp; greater sensitivity for mutant PI3K&alpha; isoforms than wild-type PI3K&alpha;, and preclinical studies have demonstrated the agent&rsquo;s potent proliferation inhibition activity on p110&alpha;-mutant breast cancer cell lines (IC50, 70 nM), as well as tumor growth inhibition in human breast cancer xenograft models harboringPIK3CAmutations.²⁵

In June 2018, the company responsible for developing the drug decided not to pursue an FDA submission based on data from the phase III SANDPIPER trial, which showed that taselisib and fulvestrant improved PFS by a modest 2 months in patients with HR-positive, HER2-negative breast cancer but resulted in more toxicity.^26,27

&ldquo;[These] findings are proof that targeting this pathway in breast cancer is effective; however, the benefits to patients are more modest than we had hoped for,&rdquo; said Jos&eacute; Baselga, MD, PhD, the study&rsquo;s lead author, who presented the SANDPIP- ER data at the 2018 ASCO Annual Meeting.²⁷Still optimistic about the potential role of this class of agents, Bardia said that results of trials testing taselisib in this patient population &ldquo;[highlight] the therapeutic role of PI3K inhibitionfor PIK3CA-mutant tumors, but also the need to carefully weigh toxicity considerations.&rdquo;

Alpelsib

An orally bioavailable PI3K&alpha;-selective inhibitor, alpelisib has demonstrated higher efficacy (IC50, about &nbsp;4 &nbsp;nM) &nbsp;and &nbsp;wider &nbsp;safety &nbsp;profile than the pan-class I PI3K inhibitor buparlisib in patients with PIK3CAmutations.²⁸

The alpelisib approval was based on data from the phase III SOLAR-1 trial, which evaluated fulvestrant with either alpelisib or placebo in patients with HR-positive, HER2-negative breast cancer who received prior treatment with endocrine therapy.7 In the cohort of patients withPIK3CA-mutated cancer (n = 341), PFS was 11.0 months (95% CI, 7.5-14.5) in the alpelisib group compared with 5.7 months (95% CI, 3.7-7.4) in the placebo group (hazard ratio, 0.65; 95% CI, 0.50-0.85;P<.001).²⁹

The overall response rate among all the patients in the cohort withPIK3CA-mutated breast cancer was greater with alpelisib at 26.6% versus placebo at 12.8%.

Concomitant with&nbsp; the&nbsp; approval&nbsp; of &nbsp;alpelisib, the FDA approved the companion &nbsp;diagnostic test therascreen PIK3CA RGQ PCR Kit (Qiagen) to select patients who havePIK3CAmutations.⁷In their review of recent advancements in the treatment of metastatic breast cancer, the authors led by Marie-France Savard, MD, said, &ldquo;The results of SOLAR-1 represented a notable milestone in precision medicine and for the use of PI3K inhibitors in metastatic breast cancer.&rdquo;³⁰

PARP Inhibitors

The synthetic lethality invoked by PARP inhibition in the background ofBRCA1/2mutations, present in 5% to 10% of patients who have received a diagnosis of breast cancer,³¹forms the basis for clinical use of PARP inhibitors in treatment of breast and other cancers characterized by mutations/defects in the DNA-repair pathway. In 2018, 2 PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), were approved for deleterious or suspected deleterious germlineBRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer.3^2,33

Olaparib

The FDA&rsquo;s first approval of a treatment for patients with gBRCAm HER2-negative metastatic breast cancer was based on data from the OlympiAD trial, which demonstrated that PARP inhibitor monotherapy provided a significant benefit over standard therapy among patients with HER2-negative gBRCAm metastatic breast cancer.³¹

Subsequent analyses indicated no statistically significant improvement in OS with olaparib; however, potential for meaningful OS benefit among patients who had not received chemotherapy for metastatic disease was noted, with no evidence of cumulative toxicity during extended exposure.³⁴

At this year&rsquo;s ASCO meeting, data from the phase II GeparOLA trial of olaparib plus paclitaxel followed by epirubicin/cyclophosphamide as neoadjuvant treatment of HER2-negative early breast cancer with homologous recombination deficiency (HRD) indicated that olaparib may have expanded clinical utility in certain patient subgroups (FIGURE).3⁵Stratified sub-group analysis showed higher pathologic complete response rates with the olaparib regimen in the cohorts of patients <40 years and in HR-positive patients.³⁵

&ldquo;In the subgroup analysis, which are hypothesis generating, we could see a pronounced effect in favor of olaparib in HR-positive tumors, in patients who were younger than 40 years, and in patients who had an HRD score [that] was high with a mutation in theBRCA1orBRCA2gene,&rdquo; said Peter A Fasching, MD, lead author. &ldquo;The results are good enough to pursue this treatment option further in the neoadjuvant setting.&rdquo;

Talazoparib

Talazoparib has been shown to exhibit a high degree of potency and oral bioavailability, com- pared with other clinical PARP&nbsp; inhibitors.³¹Its FDA approval was based on data from the pivotal EMBRACA study, in which 431 patients withgBRCAmHER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive talazoparib or physician&rsquo;s choice of chemotherapy. The median PFS was significantly longer in the talazoparib group than in the standard-therapy group, at 8.6 months and 5.6 months, respectively (hazard ratio, 0.54; 95% CI, 0.41-0.71;P<.001).³³

Although the PARP inhibitor regulatory approval is currently restricted to patients withBRCAmutations, studies have indicated that other mutations may also render tumors sensitive to PARP inhibitors, pointing to their potential beyond the context ofBRCAmutations.³⁶

Data from a proof-of-concept phase II study, which evaluated talazoparib monotherapy in patients with advanced HER2-negative breast cancer or other solid tumors with a germline or somatic alteration in homologous recombination pathway genes not includingBRCA1/2, were recently reported at the 2019 ASCO Annual Meeting. In this study, patients with measurable disease and at least 1 prior therapy for advanced HER2-negative tumors with a mutation in 1 of the DNA-repair genes were treated with talazoparib until disease progression.³⁷

&ldquo;We know based on basic&nbsp; science, as well as clinical trials in other&nbsp; disease&nbsp; settings, that there are a number of mutations outside canonicalBRCA1/2that could potentially lead to HRD and therefore, through similar mechanisms, sensitize [the tumor] to PARP inhibitor therapy,&rdquo; Gruber said. &ldquo;This trial was designed to survey for those mutations,&nbsp; identify&nbsp; them in metastatic biopsies, and select patients for treatment based on this biomarker. The relevance is that you have a certain set of patients with mutations aside fromBRCA1/2who could be good candidates for PARP inhibitor therapy.&rdquo; Of 13 patients with breast cancer, which included 1 patient with triple-negative disease, 4 had a partial response (PR) to therapy and 3 had stable disease (SD) &ge;6 months, for a clinical benefit rate of 54%. Of those, 4 patients (3 PRs and 1 SD &ge;6 months) had mutations ingPALB2, suggesting that this and other HRD alterations may be useful biomarkers for predicting talazoparib response.³⁷

&ldquo;There does seem to be a signal for gPALB2 mutations, [and] there is possibly also a signal forCHEK2mutations,&rdquo; Gruber said. &ldquo;All of these signals need to be identified and studied more carefully in further trials.&rdquo;

The antitumor effects of PARP inhibition on cancers with defects in other DNA-repair pathway genes, and even in those without deficits in DNA repair, suggest a possible broader role for PARP inhibitors.³⁶The problem of identifying and incorporating predictive biomarkers that may distinguish patients likely to respond to PARP inhibitors and other targeted monotherapies or combinations is currently being unraveled.

Utility of Genomic Biomarkers in ER-Positive Tumors

Given the significant challenge of primary or secondary resistance to endocrine therapy, biomarkers predictive of early progression on endocrine therapy and of response to new and emerging targeted therapies are of great interest.

A recent report described analysis of somatic mutations, assessed with a 17-gene panel, in baseline plasma samples from the phase III PALOMA-3 trial, which compared fulvestrant plus either palbociclib or placebo. Analysis of associations between mutations and copy number aberrations to clinical characteristics and PFS indicatedTP53mutation,FGFR1amplification, and tumor purity in plasma as markers for early progression.³⁸

Ben O&rsquo;Leary, MBBS, who presented the data&nbsp; at ASCO&rsquo;s 2019 meeting, said, &ldquo;These results in the future could perhaps inform clinical trials in advanced ER-positive breast cancer to identify a high-risk group of patients that may require escalation of therapy.&rdquo;

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