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 » Introduction
 »  Hormone receptor...
 »  Treating HER2-ne...
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 »  PI3K/AKT/mTOR in...
 » Chemotherapy
 » Chemotherapy
 » Other Therapies
 »  Unmet need in th...
 »  Role of PARP inh...
 »  Mechanism of act...
 »  Treatment of g
 »  PARP inhibitors ...
 »  PARP inhibitors ...
 »  PARP inhibitors ...
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REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 130-141
 

Management of human epidermal growth factor receptor 2–negative metastatic breast cancer: Role of poly adenosine diphosphate (ADP-ribose) polymerase inhibitors


1 Department of Medical Oncology, Medanta - The Medicity, Gurugram, Haryana, India
2 Department of Medical Oncology, Dinanath Mangeshkar Hospital, Pune, Maharashtra, India
3 Department of Medical Oncology, Max Superspeciality Hospital, Saket, New Delhi, India
4 Department of Medical Oncology, TMC, Kolkata, West Bengal, India

Date of Submission08-Jan-2021
Date of Decision22-Mar-2021
Date of Acceptance09-Aug-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Ashok Kumar Vaid
Department of Medical Oncology, Medanta - The Medicity, Gurugram, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_30_21

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 » Abstract 


Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.


Keywords: HER2-negative breast cancer, HR-positive HER2-negative breast cancer, olaparib, PARP inhibitors, talazoparib, TNBC


How to cite this article:
Vaid AK, Deshmukh C, Rohatgi N, Ghosh J. Management of human epidermal growth factor receptor 2–negative metastatic breast cancer: Role of poly adenosine diphosphate (ADP-ribose) polymerase inhibitors. Indian J Cancer 2022;59, Suppl S1:130-41

How to cite this URL:
Vaid AK, Deshmukh C, Rohatgi N, Ghosh J. Management of human epidermal growth factor receptor 2–negative metastatic breast cancer: Role of poly adenosine diphosphate (ADP-ribose) polymerase inhibitors. Indian J Cancer [serial online] 2022 [cited 2022 May 22];59, Suppl S1:130-41. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/130/340523





 » Introduction Top


In 2018, a total of 2,088,849 breast cancer (BC) cases and 626,679 BC-related deaths were reported globally.[1] India, USA, and China accounted for one third of this burden.[2] In fact, BC is the leading cancer site in Indian women.[3]

BC is a heterogeneous cancer based on receptor expression (positive/negative). The hormone receptors (HR-positive), namely, estrogen receptors (ER) and progesterone receptors (PR) are expressed within the cells, whereas the human epidermal growth factor receptor 2 (HER2) receptors are expressed on the cell surface.[4] The detailed molecular and immunohistochemistry classification of BC is provided in [Table 1].[5]
Table 1: Classification of breast cancer[5]

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Among the newly diagnosed BC, approximately 6% to -10% are Stage IV or de novo metastatic breast cancers (MBC).[6] The burden of BC metastasis, and not the primary tumor, is responsible for patient mortality.[7] Also, distant metastasis to bone, brain, and viscera leads to a negative impact on patients' physical functioning, work productivity, and quality of life (QoL).[8]

Out of all the MBC subtypes, ER-positive/HER2-negative is the most common and majorly incurable. The median overall survival (OS) of patients with this cancer is reported to be 24.8 months (95% confidence interval [CI] 21.3–30.3).[8] Though endocrine therapy (ET) remains the backbone of treatment in HR-positive/HER2-negative BC,[9],[10] patients may eventually need chemotherapy or targeted therapies such as cyclin-dependent kinase (CDK) 4/6 inhibitors (e.g. palbociclib) and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi, e.g. olaparib).[10],[11]

About 5% to -10% of BCs are hereditary, and 30% of them harbor BRCA1/2 mutations.[12] Germline BRCA mutations (gBRCAm) play a significant role in BC, but the role of sporadic BRCA mutation is not yet discernible.[13] Furthermore, triple-negative breast cancer (TNBC, i.e. ER-negative, PR-negative, and HER2-negative) is more aggressive with higher local recurrence (P = 0.001) and more likely to be BRCA mutant (P = 0.019) than HER2-positive/ER-positive BC.[2] Women with gBRCA1m have a high risk of developing high-grade BCs and TNBC.[14]

An Indian meta-analysis of 17 cross-sectional studies in the year 2016 reported that 31% of the study population had TNBC.[4] Systemic chemotherapy has been the treatment of choice in TNBC as no targeted therapies were available until now. However, with the emergence of positive data on olaparib and its approval, the treatment landscape in TNBC has begun to change.[13],[15],[16]

This review discusses the current concepts in the management of HER2-negative MBC, including TNBC, and how the management concept has changed with the advent of PARPi.


 » Hormone receptor status and treatment options Top


Approximately 1% to 4% of BC is ER-negative/PR-positive. This subtype is rare and not reproducible, and it is not covered in this review.[17]

About 75% to 80% of BCs are ER/PR-positive and being estrogen driven, they are treated with ETs. These include selective estrogen receptor modulators (SERMs; tamoxifen and raloxifene); aromatase inhibitors (AIs; letrozole, anastrozole, and exemestane); gonadotropin-releasing hormone (GnRH) agonists (leuprorelin and goserelin); or selective estrogen receptor degraders (SERDs; fulvestrant).[9],[16],[18]


 » Treating HER2-negative metastatic breast cancer Top


HER2-negative MBC is heterogeneous, comprising of both HR-positive and HR-negative BC (or TNBC), and therefore has various therapeutic options and treatment challenges.[6]

Treatment of HR-positive HER2-negative metastatic breast cancer

Endocrine monotherapy

The choice of ET (SERMs, SERDs, and AIs) is mainly based on menopausal status. Other factors considered while choosing ET include prior adjuvant therapy, comorbidities, drug safety profile, and patient preference.[19] However, there is no consensus on ET sequencing in MBC because of its heterogeneous nature and unique patient characteristics.[19],[20]

In premenopausal patients, ovarian ablation is routinely practiced along with ET. Combining ovarian ablation with tamoxifen via a luteinizing hormone-releasing hormone agonist (goserelin or buserelin) in a first-line setting demonstrated significantly increased overall survival (OS; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.63–0.96, P = 0.02), and prolonged progression-free survival (PFS; HR 0.70, 95% CI 0.59–0.85) compared with ovarian ablation alone.[21] In postmenopausal women, AIs have largely replaced tamoxifen as first-line therapy because estrogen synthesis occurs peripherally via aromatization. Hence, AIs give a better overall response rate (ORR), disease control rate, and time to progression (TTP) than tamoxifen.[22]

SERDs represent another first-line option for ET in postmenopausal women and have a proven PFS benefit over AIs in ET-naïve patients.[23] Fulvestrant when compared with anastrozole demonstrated longer TTP and decreased risk of progression in the FIRST (Fulvestrant fIRst-line Study). Also, fulvestrant demonstrated longer PFS than anastrozole (16.6 vs. 13.8 months, P = 0.048) in ET-naïve patients in the FALCON (fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer) trial.[24],[25] Another possible benefit of SERDs is overcoming ESR1 mutations. This was demonstrated in the study of faslodex with or without concomitant arimidex vs exemestane following progression on non-steroidal aromatase inhibitors (SoFEA) study, where patients with ESR1-mutated tumors treated with exemestane had significantly worse outcomes than those treated with fulvestrant (HR 0.52, 95% CI 0.30–0.92, P = 0.02).[26] However, the response rates are low in those patients previously treated with ET.

Endocrine combination therapies

Approximately 40% of the patients show intrinsic or acquired resistance to ET. Loss of ERα, mutation of ER genes (including ESR1 mutations), dysregulation of cell cycle progression or PI3K/AKT/mTOR pathway, coregulator modulation, and other such mechanisms have been implicated for ET resistance.[8],[10],[27],[28] Thus, for patients not responding to ET alone, combination therapies are tried and have now moved to the first line given the doubling PFS and manageable adverse event (AE) profile, not only for ET-resistant patients.

ET + ET combination therapies

One possibility is combining various ETs. However, various trials comparing ET combinations have revealed inconsistent results in different clinical settings. In FACT (Fulvestrant and Anastrozole Combination Therapy) trial, fulvestrant 250 mg-anastrozole failed to show any significant improvement in TTP or OS as compared with anastrozole alone in ET-treated MBC patients.[29] However, in the SWOG (Southwest Oncology Group) S0226 trial, the same combination demonstrated an improved PFS and OS over anastrozole alone in untreated metastatic disease (PFS = 15.0 vs. 13.5 months; P = 0.007 and OS = 49.8 vs. 42.0 months; P = 0.03).[30],[31] In the SoFEA trial, fulvestrant 250 mg-anastrozole demonstrated no significant difference in the PFS and OS as compared with fulvestrant 250 mg-placebo or exemestane alone in MBC patients progressing on prior AIs.[32] Similarly, a Cochrane review (n = 4,514 MBC patients) demonstrated no benefit of first- or second-line fulvestrant and ET combinations; however, results should be interpreted with caution due to the low dose of fulvestrant used in these studies.[33]

ET + targeted agent combination therapies

Combining ET with a targeted agent has fewer side effects than a combination with chemotherapy. Therefore, ETs have been combined with targeted agents such as CDK4/6 inhibitors or PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/threonine protein kinase B/mammalian target of rapamycin) inhibitors in HR-positive/HER2-negative MBC.


 » CDK4/6 Inhibitors Top


CKD4/6 inhibitors in combination with ET are approved therapies as first- and second-line settings in HR-positive/HER2-negative MBC.

Based on the results of the PALOMA-2 (Postmenopausal Women With ER+/HER2-Advanced Breast Cancer) and PALOMA-3 trials, palbociclib was approved in combination with letrozole as first-line therapy for postmenopausal women and in combination with fulvestrant in patients progressing on prior ET.[34],[35] The PALOMA-3 trial demonstrated superior median PFS in the palbociclib–fulvestrant group versus placebo–fulvestrant group (9.5 vs. 4.6 months; HR 0.46, 95% CI 0.36–0.59, P < 0.0001).[34] However, OS results demonstrated nonsignificant benefit of palbociclib–fulvestrant (34.9 months, 95% CI 28.8–40.0) over placebo–fulvestrant (28.0 months, 95% CI 23.6–34.6; absolute difference, 6.9 months; HR for death, 0.81; 95% CI 0.64–1.03; P = 0.09). In patients who were sensitive to previous ET (about 80% of the study population), the median OS was 39.7 months (95% CI 34.8–45.7) and 29.7 months (95% CI 23.8–37.9) in the palbociclib–fulvestrant and placebo–fulvestrant group, respectively (absolute difference, 10.0 months; HR 0.72; 95% CI 0.55–0.94).[36]

Ribociclib in combination with fulvestrant or AI was approved in the frontline setting in postmenopausal women with HR-positive/HER2-negative MBC. Additionally, ribociclib with fulvestrant was also approved for disease progression on ET.[37],[38] In the Phase III mammary oncology assessment of LEE011's (Ribociclib's) efficacy and safety (MONALEESA-2) and MONALEESA-3 trials, the PFS was significantly longer in the ribociclib–AI group and ribociclib-fulvestrant group, respectively, than in the placebo group (P = 3.29 × 10-6 for superiority and P < 0.001, respectively).[39],[40] Recently, the U.S. Food and Drug Administration (FDA) expanded the ribociclib label in combination with AI as initial treatment in pre-/perimenopausal women with HR-positive/HER2-negative MBC. The approval was based on the Phase III MONALEESA-7 trial demonstrating roughly 10-month improvement in PFS in the ribociclib–AI arm versus AI alone (23.8 vs. 13.0 months; HR 0.55, 95% CI 0.44–0.69; P < 0.0001).[41]

Abemaciclib is the third CDK4/6 inhibitor approved by FDA. Abemaciclib–fulvestrant combination demonstrated a significantly longer PFS than fulvestrant alone in the Phase III MONARCH-2 trial after progression on prior ET (P < 0.001).[42] Similarly, abemaciclib–AI combination showed improved PFS compared with AI alone (P < 0.001) in Phase III MONARCH-3 trial.[43]

Overall, CDK4/6 inhibitors have been shown to improve PFS in both the first and second lines. Long-term data are still expected, but two Phase III trials showed encouraging OS data especially in endocrine-sensitive patients. PALOMA-3 showed nonsignificant but clinically meaningful OS benefit with fulvestrant–palbociclib versus placebo–palbociclib (34.9 vs. 28.0 months; HR 0.81; 95% CI 0.64–1.03; P = 0.09), whereas MONALEESA-7, with an 80% power to detected a OS difference, showed a significant benefit at 42 months of follow-up (estimated OS rates for ribociclib-ET vs. placebo-ET were 70.2% vs. 46.0%, respectively).[36],[44] However, OS is difficult to interpret, given the long and complex trajectory of MBC. CDK4/6 inhibitors have high and rapid response rates and can therefore replace chemotherapy in patients with an advanced visceral disease if there is no true “visceral crisis.” Additionally, CDK4/6 inhibitors could be used in patients developing resistance due to ESR1 and PI3KCA mutations among others.[10] However, since approximately 20% of patients may not respond to CDK4/6 inhibitors and those who respond can develop resistance, other therapies will be required for managing the disease.


 » PI3K/AKT/mTOR inhibitors Top


The PI3K/AKT/mTOR pathway, or the PAM pathway, is frequently activated in BC and treated with PAM inhibitors.

mTOR inhibitors

Everolimus in combination with exemestane was the first FDA-approved mTOR inhibitor in postmenopausal BC after AI (letrozole or anastrozole) failure. In the European Union, everolimus has been approved to treat recurrence or disease progression after AIs in women without the symptomatic visceral disease.[45] In the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) study, the addition of everolimus to exemestane significantly prolonged PFS (6.9 vs. 2.8 months, P < 0.001) than exemestane alone but the combination arm had higher treatment-related AEs and treatment discontinuations. Therefore, a careful benefit–risk assessment is required before starting treatment.[45]

Patients being treated with mTOR inhibitors have demonstrated PFS benefit when added to ET in the endocrine-resistant setting, but treatment discontinuations occur due to AE.[45] But the OS was nonsignificant, especially in the ESR1 subgroup.[46]

PI3K/AKT inhibitors

Though no PI3K inhibitors have been approved so far, several of them are in the later stages of development.[10] Buparlisib (BKM120), the most studied, has demonstrated improved PFS in Phase III Buparlisib breast cancer clinical evaluation (BELLE-2) (NCT01610284) and BELLE-3 (NCT01633060) trials of MBC refractory to AI or AI + mTOR inhibitor, respectively (P < 0.001 for both trials).[47],[48] Similarly, in the Phase III SANDPIPER trial, taselisib (GDC-0032)–fulvestrant improved PFS compared with fulvestrant or placebo in the PIK3CA-mutated BC arm but not in the wild-type arm (P = 0.0037).[49]

Recently published results of Phase III SOLAR-1 trial in men or postmenopausal women with HR-positive/HER2-negative advanced BC demonstrated a median PFS of 11.0 months and 5.7 months (HR 0.65, 95% CI 0.50–1.25, P = 0.00065) in the alpelisib–fulvestrant versus placebo–fulvestrant groups, respectively, in patients harboring a PIK3CA mutation. The ORR was 36% and 16% in the alpelisib–fulvestrant and placebo–fulvestrant groups, respectively (P = 0.0002). No benefit was observed for alpelisib–fulvestrant in the cohort without PIK3CA-mutated cancer.[50]

AKT inhibitors have not yet been approved, but clinical investigations are giving encouraging results especially for patients with PIK3CA/AKT1/PTEN alterations. In the Phase II PAKT trial in first-line TNBC, median PFS in patients with PIK3CA/AKT1/PTEN alterations increased in the AKT inhibitor capivasertib (AZD5363)–paclitaxel group versus placebo–paclitaxel groups (9.3 vs. 3.7 months; HR 0.30; two-sided P = 0.01). No treatment benefit was seen in the nonaltered group.[51],[52] Ipatasertib, another AKT inhibitor, in combination with paclitaxel demonstrated a significantly better PFS (9.0 months vs. 4.9 months; HR 0.44; 95% CI 0.20–0.99; P = 0.041) in TNBC first-line patients in the PIK3CA/AKT1/PTEN alterations subgroup of the Phase II LOTUS (Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic TNBC) and a trend to OS benefit (interim results, 23.1 months vs. 18.4 months) over paclitaxel alone in locally advanced or metastatic TNBC patients in the intent-to-treat (ITT) population. Ipatasertib is now being tested in the Phase II/III IPATunity130 trial (NCT03337724) in this subset of BC not eligible for ET but exposed to prior PAM inhibitor.[53],[54]


 » Chemotherapy Top


Cytotoxic chemotherapy in HR-positive/HER2-negative MBC is usually started when BC progresses rapidly on ET and is at risk of compromising organ functions. Chemotherapy is started in these patients with the goal to return to ET once the visceral crisis subsides.[55]

Treatment of TNBC

Another subset of HER2-negative BC is TNBC, for which chemotherapy has been the primary line of management until now. Of the targeted therapies, only olaparib[56] and talazoparib[57],[58] (PARPi) were recently approved by FDA for treatment of gBRCAm HER2-negative MBC (discussed in detail later). This is documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).


 » Chemotherapy Top


Neoadjuvant or adjuvant chemotherapy remains the key systemic treatment in early TNBC. Anthracyclines and taxanes comprise the standard of care, primarily chosen based on the clinical or pathologic stage of the disease.[59] Tumors harboring a BRCA mutation, including TNBCs and other HER2-negative MBC, are highly sensitive to drugs causing deoxyribonucleic acid (DNA) double-strand breaks (DSBs) such as alkylating agents and platinum compounds.[59] Common chemotherapeutic agents used in the first, second, and later lines of management of HER2-negative MBC (including TNBC) are platinum salts (cisplatin, carboplatin), anthracyclines (epirubicin, doxorubicin), taxanes (docetaxel, paclitaxel, and nab-paclitaxel), capecitabine, eribulin, gemcitabine, vinorelbine, ixabepilone, and anthracenedione (mitoxantrone).[9],[20],[59]

The principal disadvantage of cytotoxic chemotherapy drugs is their adverse effects and waning efficacy over time warranting subsequent lines of therapy.


 » Other Therapies Top


Targeted therapies being tested in TNBC include PARPi and immunotherapies such as PD1 or PDL-1 inhibitors.[56] PARPi have been elucidated later in the review.

Immunotherapy

An exploratory analysis of the Phase III IMpassion130 placebo-controlled trial (NCT02425891) had demonstrated that PD-L1 expression was a very reliable predictor of response. The atezolizumab–nab-paclitaxel combination demonstrated no benefit over the placebo–nab-paclitaxel combination in patients with PD-L1 negative metastatic TNBC.[60] Atezolizumab plus nab-paclitaxel received accelerated approval from the FDA on March 18, 2019, for the treatment of adults with unresectable, locally advanced, or metastatic, PD-L1-positive TNBC based on IMpassion130 trial in 902 previously untreated patients with metastatic TNBC. The trial demonstrated a median PFS benefit in PD-L1-positive patients in the atezolizumab–nab-paclitaxel versus placebo–nab-paclitaxel group (7.4 vs. 4.8 months; HR 0.60, 95% CI 0.48–0.77; P < 0.0001). ORR in patients with confirmed response was 53% versus 33% in atezolizumab versus placebo arms, respectively.[61]

According to the recently published second interim OS analysis as of January 2, 2019 (data cutoff), the median OS difference between the two arms did not reach statistical significance in the ITT population.[62]

On the other hand, in a Phase II study (NCT03051659), pembrolizumab–eribulin mesylate combination failed to improve PFS over eribulin mesylate in both ITT and PD-L1-positive HR-positive MBC patients.[63]

Therefore, the benefit of immunotherapy combinations in HR-positive/HER2-negative BC remains to be seen.[56]


 » Unmet need in the treatment of HER2-negative metastatic breast cancer Top


HR-positive/HER2-negative MBC remains incurable despite several therapies.[8] Thus, there is a need for targeted therapy and novel combinations (based on endocrine and targeted therapy) in HER2-negative subset to optimize the treatment cost and outcomes.[8] In addition, patient selection and sequencing of available therapies are still unclear.

Due to the waning efficacy of subsequent-line ETs, there is a significant unmet need to enhance the efficacy of these later-line ETs. Most patients with ER-positive/HER2-negative MBC need palliative chemotherapy during the course of the disease, but each successive line of chemotherapy is less efficacious than the previous one.[8] Thus, there is a need to delay the time to onset of endocrine and CDK4/6 inhibitor resistance as this may help in delaying cytotoxic chemotherapy.[8]

Discussing all the unmet needs of HER2-negative MBC is beyond the scope of this review; however, we will discuss how PARPi have been useful in overcoming some of the unmet needs of gBRCAm HER2-negative BC in the coming sections.


 » Role of PARP inhibitors in the treatment of gBRCAm HER2-negative breast cancer Top


PARPi can be profoundly useful in TNBC due to this cancer's high genomic instability.[15],[64] Various PARPi under clinical investigation include olaparib (FDA-approved in December 2014 for gBRCAm ovarian cancer; and in January 2018 for gBRCAm HER2-negative MBC), talazoparib (FDA-approved in October 2018 for deleterious or suspected deleterious gBRCAm, HER2-negative locally advanced or MBC), niraparib (FDA-approved in March 2017 for recurrent platinum-sensitive ovarian cancer, regardless of BRCA status), and rucaparib (FDA-approved in December 2016 for gBRCAm platinum-sensitive ovarian cancer). Among them, olaparib and talazoparib are the two most widely investigated drugs in HER2-negative MBC.[57],[65],[66],[67]


 » Mechanism of action of PARP inhibitors Top


Cell death can occur if its damaged DNA is not repaired. The repair of DNA occurs at two levels: single-stranded breaks (SSBs) and DSBs. While SSBs are repaired by base excision repair (BER), nucleotide excision repair, or mismatch repair, DSBs are repaired through BRCA1- and BRCA2-dependent homologous recombination.[68]

PARPi compromise the BER pathway of SSB repair. Unrepaired SSBs encounter the DNA replication forks leading to DSB formation and accumulation. This results in the collapse of the DNA replication forks and cell death [Figure 1].[68],[69] PARP protein-dependent DNA repair pathways act by PARP trapping and prevent repair protein recruitment to sites of DNA repair. Thus, PARPi play a crucial role in improving cancer cell survival in gBRCAm BC and in BC with acquired functional impairment of homologous recombination.[15],[64],[68]
Figure 1: Mechanism of action of PARP inhibitors through SSBs and PARP trapping[69]. DNA = Deoxyribonucleic acid; DSB = double-strand breaks; HR = homologous recombination; PARG = poly (ADP-ribose) glycohydrolase; PARP = poly (ADP-ribose) polymerase; SSB = single-strand break

Click here to view


Olaparib is a potent PARP-1 and -2 inhibitor and niraparib is a broad PARPi.[64] Arun et al.[70] reported that olaparib is one of the PARPi that induces complete cell death in 95% to 99% of TNBC cell lines and the elimination of mitochondria through autophagy.


 » Treatment of gBRCAm HER2-negative breast cancer with PARP inhibitors Top


Efficacy of PARP inhibitors in the treatment of gBRCAm metastatic HER2-negative breast cancer

PARP inhibitors monotherapy

Olaparib

Olaparib is recently approved for gBRCAm HER2-negative MBC treated with less than or equal to two prior lines of chemotherapy in a neoadjuvant, adjuvant, or metastatic setting; HR-positive/HER2-negative patients should either have received prior ET or should be ineligible for it.[66]

Olaparib in advanced disease in breast cancer (OlympiAD), the landmark trial that led to the approval of olaparib demonstrated significantly (P < 0.001) improved PFS in gBRCAm HER2-negative MBC treated with less than or equal to two prior lines of chemotherapy who were carboplatin naïve and did not permit treatment with carboplatin during the trial also showed considerably higher response rate (59.9%) as compared with the standard therapy (28.8%).[71] Furthermore, the Phase III olaparib in adjuvant setting in breast cancer (OlympiA) trial (NCT02032823) is evaluating invasive disease-free survival (DFS) after adjuvant 1-year olaparib monotherapy, which is given after standard neoadjuvant chemotherapy and local treatment in high-risk early TNBC with gBRCA1/2m.[72]

Talazoparib

EMBRACA trial (Phase III) evaluated the effect of talazoparib versus standard therapy in patients with HER-2 negative advanced BC and gBRCA1/2m treated with unlimited prior hormonal or targeted therapies but no more than three prior chemotherapy regimens. Patients on talazoparib had a significantly longer PFS (8.6 vs. 5.6 months) and ORR (62.6% vs. 27.2%) than standard therapy (P < 0.001 for each).[73] Based on these results, FDA recently approved talazoparib for the treatment of gBRCAm, HER2-negative locally advanced or MBC.[57]

Olaparib or talazoparib versus chemotherapy

In 2018, a meta-analysis of the OlympiAD (olaparib) and the EMBRACA (talazoparib) trials evaluating the role of single-agent PARPi for gBRCAm HER2-negative MBC showed that PARPi significantly improved the PFS and ORR as compared with chemotherapy (P < 0.001 for each). However, there was no significant difference in OS between them (P = 0.120). Furthermore, time to QoL deterioration was significantly delayed in patients treated with PARPi than in the chemotherapy group (HR 0.40; 95% CI 0.29–0.54).[11] The ESMO (European Society for Medical Oncology) and the NCCN (National Comprehensive Cancer Network) guidelines, therefore, recommend olaparib or talazoparib for the treatment of BRCA-associated advanced BC after progression on ET even though the PARPi trials did not allow prior platinum.[19],[74]

Rucaparib

The ongoing Phase II RUBY (NCT02505048) trial is investigating the clinical efficacy of rucaparib in patients with metastatic gBRCA-wild type, HER2-negative MBC.

Niraparib

The ongoing Phase III BRAVO (NCT01905592) trial aims to compare PFS after niraparib with physician's choice of cytotoxic chemotherapy in gBRCA1/2m, HER2-negative metastatic or locally advanced incurable BC after less than or equal to two cytotoxic regimens.[75]


 » PARP inhibitors in combination with chemotherapy Top


PARPi in combination with cytotoxic chemotherapy and/or radiotherapy have demonstrated high toxicities overweighing the efficacy achieved.[64] However, some trials are showing promising results and are discussed here.

Olaparib and chemotherapy

The Phase II GeparOLA (NCT02789332) in HER2-negative early BC with homologous recombination deficiency (HRD) showed a pathological response rate (pCR) of 55.1% (90%CI 44.5–65.3%) in olaparib–chemotherapy group and 48.6% (90% CI 34.3–63.2%) chemotherapy-alone group. Higher pCR rates were observed in patients <40 years of age and in HR-positive patients treated by olaparib–chemotherapy. However, a pCR rate of ≤55% could not be excluded in the olaprarib–paclitaxel arm.[76] Ongoing Phase II/III PARTNER (NCT03150576) study aims to evaluate the efficacy and safety of adding olaparib to neoadjuvant platinum-based chemotherapy in TNBC or gBRCAm BC. Results from this trial may throw light on whether individually tolerable and effective drugs will be equally safe and effective in combination.[77]

Veliparib and chemotherapy

Neoadjuvant veliparib and carboplatin (VC) was evaluated in the Phase II investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2 (I-SPY 2) trial in addition to the standard chemotherapy. The most significant benefit from VC therapy versus standard therapy was seen in TNBC and high-risk BC group with a pCR rate of 52% versus 24%.[78]

Veliparib trials failed to show efficacy in TNBC. The Phase III BrighTNess trial (paclitaxel–carboplatin–veliparib versus paclitaxel–carboplatin vs. paclitaxel alone in early TNBC) demonstrated higher pCR in the paclitaxel–carboplatin–veliparib group compared with paclitaxel-alone group (53% vs. 31%, P < 0.0001), but not compared with paclitaxel–carboplatin group (53% vs. 58%, P = 0.36). The study showed that the addition of carboplatin and not veliparib (50 mg orally BD [twice daily]) led to pCR increase, although the study was not designed for a comparison of pCR between paclitaxel plus carboplatin group and paclitaxel-alone group.[15] It may be noted that veliparib dose and schedule in BrighTNess trial were lower than the maximum-tolerated veliparib dose that could have been used in combination with carboplatin and paclitaxel.[15]

Rucaparib and chemotherapy

Currently, there are no pivotal Phase III trials investigating rucaprib in HER2-negative MBC. A Phase II study by the Hoosier Oncology Group BRE09-146 is evaluating the 2-year DFS in patients with TNBC or ER/PR-positive, HER2-negative BC with known BRCA1/2 mutations following PARP inhibition with rucaparib–cisplatin versus cisplatin alone given after preoperative chemotherapy (NCT01074970).[79]

PARPi with various new agents are being investigated in several trials as outlined below. Results of these trials may open up new ways to treat advanced HER2-negative BC unresponsive to standard therapies.


 » PARP inhibitors in combination with immune-checkpoint inhibitors Top


The Phase I/II MEDIOLA (NCT02734004) study is investigating olaparib in combination with PD-L1 inhibitor durvalumab in patients with gBRCA1/2m HER2-negative MBC.[75],[80] Another Phase II trial of olaparib in combination with durvalumab (DORA, NCT03167619) as maintenance has been initiated in 2018 in platinum-sensitive metastatic TNBC.[75]

TOPACIO/Keynote-162(NCT02657889), a Phase I/II trial is investigating niraparib with PD1 inhibitor pembrolizumab in advanced or metastatic TNBC.[81] Also, talazoparib (in combination with PD-L1 inhibitor avelumab) is being investigated in a Phase Ib/II JAVELIN PARP MEDLEY (NCT03330405) study in gBRCA1/2m or ATM-deficient BC patients.[75] Additionally, a Phase II (NCT02849496) trial is evaluating veliparib with PD-L1 inhibitor atezolizumab in patients with gBRCA1/2m TNBC.[75]


 » PARP inhibitors in combination with angiogenesis inhibitors Top


A Phase I/II trial (NCT01116648) is recruiting patients with metastatic TNBC to find the dose-limiting toxicity and maximum-tolerated dose (MTD) of olaparib in combination with vascular endothelial growth factor inhibitor cediranib maleate and compare the PFS achieved with respect to olaparib alone.[82] Another Phase I/II trial (NCT02498613) is investigating the ORR achieved with olaparib–cediranib maleate in patients with unresectable and metastatic TNBC after cytotoxic chemotherapy.[83]


 » PARP inhibitors in combination with other therapies Top


The Phase I trial (NCT02898207) is exploring the MTD of olaparib–HSP90 inhibitor onalespib combination in metastatic TNBC after greater than or equal to four cytotoxic therapies.[84] Also, a Phase I trial (NCT01623349) in patients with metastatic TNBC after the failure of greater than or equal to one cytotoxic therapy is evaluating MTD and recommended Phase 2 dose of olaparib–PI3K inhibitor (BKM120 or BYL719) combination.[85]

A Phase I trial (NCT03075462) is exploring PARPi fluzoparib with vascular endothelial growth factor receptor inhibitor apatinib in inoperable locally advanced metastatic TNBC after greater than or equal to one cytotoxic regimen.[86]

The trials investigating PARPi are presented in [Table 2].[15],[56],[59],[73],[78],[87]
Table 2: Clinical trials investigating the efficacy of PARP inhibitors in the treatment of breast cancer

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Safety of PARP inhibitors in the treatment of gBRCAm HER2-negative breast cancer

Several studies evaluating the safety of PARPi have reported anemia, decreased white cell count, dyspnea, neutropenia, nausea, fatigue, vomiting, decreased appetite, headache, diarrhea, thrombocytopenia, febrile neutropenia, and anorexia as the most commonly observed AEs with PARPi [Table 3].[15],[58],[71],[66]
Table 3: Clinical trials investigating the safety of PARP inhibitors in the treatment of breast cancer

Click here to view



 » Summary/Conclusion Top


HER2-negative subset is the most heterogeneous MBC with HR-positive and HR-negative BC (or TNBC) having different therapies and treatment challenges. Though ET is the primary treatment in HR-positive/HER2-negative patients, about 40% of the patients develop intrinsic or acquired resistance to ET. Efforts are ongoing to look at the best monotherapy and combination therapy and sequencing of therapy in HER2-negative MBC. PARPi are now emerging as one of the effective treatment options for gBRCAm HER2-negative BC both in HR-positive and TNBC settings. In fact, olaparib and talazoparib are already approved in gBRCAm HER2-negative MBC treated with prior lines of anthracycline- or taxane-based chemotherapy. Ongoing studies of PARPi combinations with various therapies will hopefully provide valuable insights for treating HER2-negative BC, and thus, results from various monotherapy and combination therapy trials are eagerly awaited.

Acknowledgments

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Turacoz Healthcare solutions in accordance with the GPP3 guidelines (http://www. ismpp.org/gpp3).

Financial support and sponsorship

AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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