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Review

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

by
Maria Clara Saad Menezes
1,
Farah Raheem
2,
Lida Mina
2,
Brenda Ernst
2 and
Felipe Batalini
2,*
1
Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA
2
Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(17), 4332; https://doi.org/10.3390/cancers14174332
Submission received: 27 July 2022 / Revised: 27 August 2022 / Accepted: 1 September 2022 / Published: 5 September 2022
(This article belongs to the Special Issue Genomic Landscape of Breast Cancer: From Primary to Metastasis)
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Abstract

:

Simple Summary

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with mutations in DNA repair genes, most commonly in the BRCA1 and BRCA2 genes. Because these tumors are unable to repair their DNA, PARPi have been used to target DNA repair pathways and are useful in the treatment of breast cancers with some of these alterations. There are two FDA-approved PARPi for patients with breast cancer—olaparib and talazoparib. The data on olaparib and talazoparib in the treatment of breast cancer are summarized in this review, and we also explore potential future applications of PARPi beyond inherited BRCA mutations.

Abstract

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

1. Introduction

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with an impaired ability to repair double-strand DNA breaks, such as those with homologous recombination repair (HRR) deficiency (HRD) [1,2]. PARP enzymes play a role in a range of cellular activities. PARP1 and PARP2 are essential for the repair of single-strand breaks in DNA. When PARP enzymes are suppressed, DNA single-strand breaks accumulate and lead to DNA double-strand breaks at replication forks. When the processes for repairing double-strand breaks are inadequate, such as in tumor cells with HRD, there is a threat to cell survival. PARPi and HRD represent a lethal combination, which is the basis of the concept of synthetic lethality, though neither is lethal alone (Figure 1) [1,2,3]. In addition to the catalytic inhibition of PARP enzymes, PARPi trap PARP1 and PARP2 at damaged DNA sites, preventing the recruitment of additional DNA repair proteins and ultimately leading to cell death [4]. Trapped PARP–DNA complexes have been shown to be more cytotoxic than the single-strand breaks generated by PARP inactivation [4]. Differences in PARP trapping potential are not correlated with the inhibition of PARP catalytic activity [4].
PARPi have been extensively studied in cancers where HRD is prevalent, including breast cancer (BC). The development of BC is linked to germline and somatic pathogenic mutations in DNA-repair genes. Approximately 10% of BC cases are familial, and half of these are due to an inherited deleterious BRCA1/2 mutation [5,6]. Familial BCs are overrepresented among women with triple-negative BC (TNBC): nearly 14% have pathogenic germline variants, and approximately 50% consist of BRCA1/2 mutations [6]. While BRCA1 and BRCA2 pathogenic variants are associated with a high risk of BC, PALB2 pathogenic variants are associated with a moderate risk of BC [7,8]. Variants in other DNA-repair genes are linked to a higher risk of estrogen-receptor-positive BC (CHEK2, ATM, and CDH1) as well as TNBC (BARD1, RAD51C, and RAD51D) [7,8]. The estimated odds ratios of BC linked with various DNA-repair mutations are shown in Table 1 [8].
For BRCA1/2 carriers with human epidermal growth factor receptor two (HER2)-negative BC, PARPi can be beneficial in the adjuvant setting for patients at high risk of recurrence [10] and in the metastatic setting [11,12]. There are twelve other FDA-approved indications for PARPi in a variety of cancers, as summarized in Table 2 [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29].
Currently, there are four FDA-approved PARPi: olaparib, rucaparib, niraparib, and talazoparib [14,15,16,17]. Olaparib and talazoparib are approved for BC patients [11,12]. In a phase II trial of rucaparib in BRCA carriers with advanced BC, there was no response among the 23 patients treated [30]. Olaparib and rucaparib have similar potencies for trapping PARP–DNA complexes [31], and all PARPi are pharmacologically similar in terms of inhibiting PARP catalytic activity. However, talazoparib is 100 times more effective at trapping PARP–DNA complexes and is more cytotoxic as a single agent than olaparib [31]. The varying initial doses of each PARPi drug reflect this relative variance in potency. The typical starting doses are 300 mg B.I.D. for olaparib; 200 or 300 mg daily for niraparib, depending on the patient’s baseline weight and/or platelet count; 600 mg B.I.D. for rucaparib; and 1 mg daily for talazoparib [14,15,16,17].
The present article reviews the key clinical trial data for the PARPi currently approved for BC—olaparib and talazoparib. We also discuss the role of PARPi in patient populations with BC harboring HRD mutations beyond BRCA.

2. Methods

We searched PubMed on 29 April 2022, for clinical studies exploring the use of PARPi in patients with BC using the following search terms: “breast” AND “Olaparib OR AZD2281 OR Talazoparib OR BMN 673”. The references of the included articles were also screened for eligible papers (Figure 2). Seventy-three trials were included and divided into the following groups: (Section 3) OLAPARIB, (Section 3.1) early-phase studies, (Section 3.2) locally advanced or metastatic BC, (Section 3.3) early-stage BC, and (Section 3.4) combination trials; (Section 4) TALAZOPARIB, (Section 4.1) early-phase studies, (Section 4.2) locally advanced or metastatic BC, (Section 4.3) early-stage BC.

3. Olaparib

3.1. Early-Phase Studies

Olaparib belongs to the N-acylpiperazine class and is made via the formal condensation of the free amino group of N-(cyclpropylcarbonyl)piperazine with the carboxy group of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid [32]. It is a PARPi that targets PARP1, PARP2, and PARP3 [14]. Increased cytotoxicity and anti-tumor activity were observed in cell lines and mice tumor models with defects in BRCA1/2, ATM, or other genes involved in DNA repair after treatment with olaparib, and this was linked with platinum responsiveness [19,20]. In terms of monotherapy, phase I trials identified the maximum tolerated dose of olaparib capsules to be 400 mg B.I.D [33,34]. The mean maximal PARP inhibition in human peripheral blood mononuclear cells and tumor tissue is 50.6% and 70.0%, respectively [35]. Based on pharmacokinetics, tolerability, and efficacy measured by tumor shrinkage, the recommended olaparib monotherapy tablet dose is 300 mg B.I.D [36,37]. Olaparib was originally available in tablets and capsules. These dosage forms are not bioequivalent and thus are not interchangeable [37]. In the United States, capsule formulation was discontinued as of 2018. Olaparib absorption is delayed with high-fat meals, but the extent of absorption is not significantly altered [38,39]. Thus, olaparib can be administered with or without food, although administration with a meal may help prevent gastrointestinal adverse events (AEs) such as nausea or vomiting [38,39]. Olaparib is a major substrate of CYP3A4 and is primarily hepatically metabolized through oxidation [40]. Concomitant administration with strong inducers and inhibitors of CYP3A4 should be avoided [41]. If administration with a strong CYP3A4 inhibitor cannot be avoided, the olaparib tablet dose should be reduced to 100 mg B.I.D [14,41]. Olaparib is the only PARPi that does not cause transaminitis [42]. Olaparib has the most extensive hepatic metabolism and should be avoided when used with other agents that affect or undergo hepatic metabolism [40,43]. Pharmacokinetic studies showed that the mean area under the receiver operating characteristic curve (AUC) and peak serum concentration (Cmax) of olaparib were increased by 15% and 13%, respectively, in patients with mild hepatic impairment [43]. However, dose adjustment for mild or moderate hepatic impairment is not necessary [40]. Approximately, 44% of olaparib is excreted in the urine, mostly as metabolites. Exposure to olaparib was shown to be increased in renal impairment. In those with mild impairment (creatinine clearance (CrCl) 51 to 80 mL/min) AUC and Cmax increased by 24% and 15%, respectively) [44]. Drug exposure increased to a higher extent (AUC and Cmax increase by 44% and 26%, respectively) with moderate impairment (CrCl 31 to 50 mL/min), which required adjusting the olaparib dose (tablets) to 200 mg B.I.D [44]. An increase in serum creatinine was also observed with olaparib (up to 99%) [45,46]. It is believed that elevations in serum creatinine might not reflect a true decline in the glomerular filtration rate or kidney insufficiency, and monitoring alternative markers, such as Cystatin C, that are not impacted by transporters of creatinine should be considered to avoid an unnecessary dose reduction of olaparib and other PARPi [42,45,46]. Secondary hematological malignancy has rarely been reported in patients treated with olaparib [47]. The median duration of therapy prior to the development of the secondary cancers was two years (range: six months to >ten years) [14].
The most common AEs with olaparib include fatigue (67%), nausea (45% to 77%; grades 3/4: ≤3%), abdominal pain (34% to 45%), anemia (23% to 44%; grades 3/4: 7% to 21%), and neutropenia (5% to 19%; grades 3/4: 4% to 6%), with rashes (5 to 15%) and pneumonitis (<1%) being less common AEs [14]. Olaparib has no clinically significant effect on the QT interval [48]. Prolonged hematologic toxicity should prompt olaparib treatment interruption and the weekly monitoring of blood counts until recovery [14]. If counts do not recover to ≤ grade 1 after four weeks, further evaluation including bone marrow and cytogenetic analyses is necessary [14].
In combination therapy studies, olaparib has been studied with bevacizumab [49], cediranib [50,51,52], paclitaxel [53,54,55], carboplatin [56,57,58,59], a carboplatin/paclitaxel combination [60,61,62], cyclophosphamide [63], liposomal doxorubicin [64], cisplatin [65], lurbinectedin [66], durvalumab [51,52,67], dacarbazine [68], eribulin [69], ceralasertib [70], onalespib [71], prexasertib [72], gemcitabine [73], a cisplatin/gemcitabine combination [74], topotecan [75], and radiation therapy [76]. Olaparib was also studied in combination with phosphatidylinositol 3-kinase (PI3K) inhibitors (PI3Ki). While combination therapy required a dose attenuation of the pan-PI3Ki BKM120 in one study [77], the combination of olaparib with the PI3Ki alpelisib was shown to be safe and effective [78]. Similarly, olaparib combination appeared to be safe with the protein kinase B inhibitor capivasertib [79,80]. Additionally, there were no clinically relevant interactions between olaparib and endocrine therapy including anastrozole, letrozole, or tamoxifen [81].

3.2. Locally Advanced or Metastatic Breast Cancer

Phase II trials demonstrated the efficacy of PARPi in patients with BC. In patients that had a median of three prior treatments with chemotherapy, Tutt et al. demonstrated an objective response rate (ORR) of 41% and 22% in BRCA carriers who received olaparib at the doses of 400 mg B.I.D. and 100 mg B.I.D., respectively [82]. Kaufman et al. reported an ORR of 12.9% in 62 BC patients who received olaparib 400 mg B.I.D. with germline BRCA mutation (gBRCA) and three or more previous lines of therapy [21]. Conversely, Gelmon et al. investigated olaparib in advanced solid tumors, and no objective responses were reported in the 26 patients with BC (16 patients with TNBC and ten patients with BRCA-mutated BC). The median of previous therapies was also three [83].
In the phase III trial OlympiAD, patients with advanced HER2-negative BC and confirmed or suspected deleterious gBRCAm who had received no more than two previous chemotherapy regimens for metastatic disease and at least one endocrine therapy for hormone-receptor-positive disease were assigned to either olaparib monotherapy or standard-of-care chemotherapy. Patients were given olaparib tablets (300 mg B.I.D.) or standard therapy with a single-agent chemotherapy of their doctor’s choice in a 2:1 ratio (capecitabine, eribulin, or vinorelbine in 21-day cycles). Olaparib increased median progression-free survival (PFS) by nearly three months (7.0 months vs. 4.2 months; hazard ratio (HR) for disease progression or death, 0.58; 95% confidence interval (CI), 0.43–0.80; p < 0.001). With olaparib, the ORR was 59.9%, and with chemotherapy, it was 28.8%. The rate of grade 3 or higher AEs was 36.6% in the olaparib group and 50.5% in the conventional therapy group. Treatment discontinuation due to toxicity occurred in 4.9% and 7.7% of patients, respectively. There were no reports of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or other secondary malignancies [12,84,85]. The FDA approved olaparib for the treatment of patients with gBRCAm and HER2-negative metastatic BC who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting, based on the findings of this study. Patients with hormone-receptor-positive disease should have received and progressed on a prior endocrine therapy [14]. The results of a recent phase IIIb trial were consistent with previous findings and reported an ORR of 50% in a similar patient population [86].

3.3. Early-Stage Breast Cancer

In the phase II PETREMAC trial, olaparib monotherapy demonstrated an ORR of 56.3% (18 out of 32) in patients who received olaparib for up to ten weeks before chemotherapy. Patients had previously untreated stage II/III TNBC with a tumor size of more than two cm (the median pretreatment tumor size was six cm) [87].
In the adjuvant setting, results from the OlympiA trial led to the FDA approval of olaparib for patients with gBRCAm in the curative intent setting. OlympiA was a randomized, double-blind, phase III trial that compared olaparib to a placebo in the adjuvant context for BRCA carriers with HER2-negative BC who had a high risk of recurrence. Patients who had received neoadjuvant chemotherapy were not allowed to receive additional chemotherapy following surgery. Patients with TNBC who received neoadjuvant chemotherapy had to have residual disease, while those who received adjuvant chemotherapy had to have positive axillary lymph node involvement or a primary tumor measuring at least two cm. Patients with a hormone-receptor-positive tumor who received adjuvant chemotherapy were required to have at least four positive lymph nodes, and those who received neoadjuvant chemotherapy were required to have not achieved a pathological complete response (pCR), with a clinical and pathological stage plus estrogen receptor status and histological grade (CPS + EG) score of at least three. The CPS + EG is a validated staging system for disease-specific survival that provides a prognosis assessment of patients with early-stage BC after treatment with neoadjuvant chemotherapy. The CPS + EG score estimates the probability of disease relapse based on pretreatment clinical stage and post-neoadjuvant CPS as well as the status of the estrogen receptor and histological grade. Scores range from zero to six, with higher scores indicating a worse prognosis [88].
At the three-year mark, in comparison to placebo, patients who received olaparib had higher rates of invasive disease-free survival (85.9% vs. 77.1%; HR, 0.58, 99.5% CI 0.41–0.82; p < 0.001) and distant disease-free survival (87.5% vs. 80.4%; HR, 0.57, 99.5% CI 0.39–0.83; p < 0.001) [10]. Grade 3 or higher AEs that occurred in the olaparib arm included anemia (8.7%), decreased neutrophil count (4.8%), decreased white-cell count (3.0%), fatigue (1.8%), and lymphopenia (1.2%). In the olaparib arm, 25% of patients had a dose reduction, compared with 5.2% in the placebo arm. The rate of MDS or AML was 0.2% (two patients) in olaparib arm versus 0.3% (three patients) in the placebo arm [10]. At a median follow up of 3.5 years, adjuvant olaparib significantly improved overall survival (OS), with a HR of 0.68 (98.5% CI 0.47–0.97; p < 0.01). The 4-year OS rate was 89.8% with olaparib vs. 86.4% with the placebo. Improvements in distant (HR 0.61; 95% CI 0.48–0.77) and invasive (HR 0.63; 95% CI 0.50–0.78) disease-free survival were sustained. There were no emergent AEs and no new cases of MDS or AML reported [89]. Based on these results, the treatment guidelines recommend one year of adjuvant olaparib for patients with HER2-negative, early-stage BC and gBRCAm who meet the criteria for high recurrence risk as defined in the OlympiA trial enrollment criteria discussed above [90].

3.4. Combination Trials

3.4.1. Olaparib and Eribulin

Yonemori et al. published a phase I/II study in advanced or metastatic TNBC that considered the combination of olaparib (tablets) with eribulin. The recommended phase II dose for olaparib was determined to be 300 mg B.I.D. and 1.4 mg/m2 for eribulin. The median number of treatments given to the 24 patients in the phase II group was 5.5 (range: 1–28). Neutropenia (83.3%), leucopenia (83.3%), anemia (41.7%), febrile neutropenia (33.3%), and thrombosis were among the grade 3 AEs (8.3%). The response rate was 29.2% (7/24; 90% Cl 14.6–47.9). Despite the anticancer effect of the combination therapy, substantial rates of febrile neutropenia limited its use in clinical practice [69]. The median PFS and OS were 4.2 months (95% CI, 3.0–7.4) and 14.5 (95% CI, 4.8–22.0), respectively. Responders were enriched for tumors with homozygous BRCA1-promoter methylation, which may improve the accuracy of identifying TNBC patients who will benefit from the olaparib/eribulin combination therapy [91].

3.4.2. Olaparib and Paclitaxel

In a randomized phase II trial, Fasching et al. compared the efficacy of paclitaxel and olaparib to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as a neoadjuvant treatment in patients with HER2-negative early BC and HRD (60.4% of patients were BRCA carriers, and the rest had a high HRD score based on the Myriad MyChoice HRD results). With paclitaxel/olaparib, the pCR rate was 55.1% (90% CI 44.5–65.3%), while with paclitaxel/carboplatin, it was 48.6% (90% CI 34.3–63.2%) [92].

3.4.3. Olaparib and Durvalumab

A phase I/II trial of durvalumab with olaparib in solid tumors was published by Domchek et al. in 2020. Patients with gBRCAm and metastatic, HER2-negative, progressing BC were included in the study. The use of up to two previous lines of chemotherapy for metastatic BC was permitted. Olaparib (tablet) at 300 mg B.I.D. was administered for four weeks, followed by an intravenous infusion of olaparib 300 mg B.I.D. and durvalumab 1.5 g every four weeks until disease progression. Thirty-four patients were enrolled, and 11 (32%) of them had grade 3 or worse AEs, with anemia (four—12%), neutropenia (three—9%), and pancreatitis (two—6%) being the most common. Three patients (9%) stopped taking the medication due to side effects, while four patients (12%) had major side effects. Major side effects included dyspnea (one event), pancreatitis (two events), and immune-mediated events at the discretion of the investigator (one event). There were no deaths due to the treatment. Among the 30 patients eligible for efficacy analysis, the ORR at week 12 was 63.3% (90% CI 48.9–80.1%), and 24/30 (80%; 90% CI 64.3–90.9%) had disease control at 12 weeks [67].

3.4.4. Olaparib, Durvalumab, and Paclitaxel

Pusztai et al. published the results of one arm of their phase II I-SPY2 adaptive platform study in 2021, which considered the combination of durvalumab and olaparib with weekly paclitaxel for the neoadjuvant treatment of stage II/III, HER2-negative BC. Weekly paclitaxel was administered with olaparib 100 mg B.I.D. on weeks one through eleven and intravenous durvalumab 1500 mg every four weeks. Weekly paclitaxel was followed by doxorubicin with cyclophosphamide in the control arm. The durvalumab/olaparib/paclitaxel arm contained 73 patients, while the standard-of-care paclitaxel control arm contained 299 patients. In all HER2-negative (20–37%), TNBC (27–47%), and hormone-receptor-positive/HER2-negative (14–28%) patients, durvalumab/olaparib/paclitaxel was linked to a higher pCR rate. In the durvalumab/olaparib/paclitaxel arm, 12.3% of patients had immune-related grade 3 AEs, compared to 1.3% in the control arm [55].

4. Talazoparib

4.1. Early-Phase Studies

Talazoparib is a heterocyclic compound with one ring that belongs to the class of phthalazines, with the molecular formula C19H14F2N6O [93]. Talazoparib is a potent PARPi, demonstrating both the strong catalytic inhibition of PARP1 and PARP2 and significant PARP trapping potential [31]. The maximum tolerated dose of talazoparib was determined to be one mg daily, but sustained PARP inhibition was reported at dosages as low as 0.60 mg/day [94,95]. Talazoparib is largely eliminated by the kidneys after limited hepatic metabolization [96,97]. Combination trials have included carboplatin, which caused significant hematologic toxicity [98]; temozolomide [99]; and irinotecan [100].
Talazoparib is only available in capsules, which can be administered with or without food [17]. Talazoparib is a major substrate of p glycoprotein/ABCB1, which is an ATP-dependent efflux pump [17]. Certain medications may inhibit or increase the serum concentration of p-glycoprotein, and screening for interactions is necessary [17]. Talazoparib undergoes minimal hepatic metabolism [96,97]. Renal excretion accounts for 69% of the drug clearance, and up to 54.6% of the drug is excreted unchanged in the urine [96,97]. Talazoparib exposure is increased by 12%, 43%, and 163%, and Cmax is increased by 11%, 32%, and 89% with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2), and severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment, respectively [96,97]. As a result, talazoparib requires a renal dose adjustment to 0.75 mg daily for moderate renal impairment (CrCl 30 to 59 mL/min) and 0.5 mg daily for severe renal impairment (CrCl 15 to 29 mL/min) [96,97]. Common AEs include decreased hemoglobin (90%; grade 3: 39%), anemia (53%; grade 3: 38%), neutropenia (35%; grade 3: 18%), thrombocytopenia (27%; grade 3: 11%), fatigue (62%), nausea (49%), headache (33%), and transaminitis (37%) [17]. A higher talazoparib concentration is linked to an increased risk of anemia and thrombocytopenia [101]. Alopecia was reported in 25% of patients treated with talazoparib [17]; however, this was classed as grade 1 (<50% hair loss that is not obvious from a distance) and was considered hair thinning. Grade 2 alopecia (>50% hair loss that is apparent from a distance) was reported in only 2.4% of patients [102,103]. Serum creatinine elevation has not been reported with talazoparib [17]. Talazoparib has less emetogenic potential (minimal to low) than olaparib, niraparib, and rucaparib, which are associated with a moderate to high emetic risk [104]. The reported rate of MDS/AML with talazoparib is less than one percent [17]. The duration of talazoparib therapy prior to the development of MDS/AML ranges from four months to five years [17].

4.2. Locally Advanced or Metastatic Breast Cancer

The ABRAZO trial examined whether talazoparib could help BRCA carriers with locally advanced or metastatic cancer who had previously been exposed to platinum treatment. Those who had previously received platinum-based chemotherapy had an ORR of 21%, while patients who had received at least three non-platinum-based regimens had an ORR of 37% [105,106]. Litton et al. published the results of the EMBRACA trial in 2018, which was a randomized, open-label, phase III trial with advanced gBRCAm BC patients who had received three or fewer cycles of chemotherapy for metastatic disease. Two hundred and eighty-seven patients were given talazoparib (one mg per day) and 144 patients were given standard single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Patients who had previously undergone platinum treatment were eligible if they had a disease-free interval of at least six months and no signs of progression on previous platinum therapy. The talazoparib group had a significantly longer PFS than the conventional therapy group (8.6 months vs. 5.6 months; HR 0.54; 95% CI, 0.41–0.71; p < 0.001) [11]. Based on the results of this study, the FDA approved talazoparib for the treatment of patients with gBRCAm and HER2-negative locally advanced or metastatic BC [17].

4.3. Early-Stage Breast Cancer

In a pilot study of talazoparib for early-stage BC, following two months of talazoparib preoperative monotherapy, all thirteen BRCA carriers included showed a decreased tumor volume. The average decrease in volume was 78% (range 30–98%). Talazoparib was well-tolerated, with no grade 4 side effects reported, and only one patient’s dose had to be reduced due to grade 3 neutropenia [107]. Litton et al. reported in 2020 that neoadjuvant talazoparib treatment for six months resulted in a pCR of 53% in patients with gBRCAm and operable stage I to III BC [108].

5. Biomarkers of Response to PARPi

To date, conflicting results for different proposed HRD biomarkers based on copy-number variations have been published. Telli et al. reported that a combined HRD score—unweighted sum of loss of heterozygosity (LOH), telomeric–allelic imbalance, and large-scale state transition scores—predicted responses in three neoadjuvant TNBC trials of platinum-containing therapy [109]. In contrast, TBCRC-030 [110] showed that the Myriad MyChoice HRD results were not predictive of pathologic responses to platinum agents. Additionally, Blum et al. [111] showed that BRCA LOH status, DNA damage response and repair gene mutational burden, and genome-wide LOH were not associated with responses to talazoparib in BRCA carriers enrolled in the EMBRACA trial.
Batalini et al. showed that mutational signature 3 (Sig3) and the genomic instability score (GIS) were associated with responses to olaparib and that Sig3 demonstrated overall better performance than GIS for identifying responders [112]. The Spanish NOBROLA trial is currently enrolling non-BRCA patients that have a high genome-wide LOH (ClinicalTrials.gov identifier: NCT03367689). The PETREMAC trials evaluated several potential biomarkers of response to PARPi: BRCAness, PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes, and programmed cell death ligand one analyses were performed on pretreatment samples. Somatic or germline mutations affecting HRR pathway genes were observed in 10/18 responders (55.6%, 95% CI 33.7–75.4), in contrast to the 1/14 in non-responders. Among tumors without HRR pathway mutations, 6/8 responders vs. 3/13 non-responders revealed BRCA1 hypermethylation (p < 0.04). Thus, 16/18 responders (88.9%, 95% CI 67.2–96.9), in contrast to 4/14 non-responders (28.6%, 95% CI 11.7–54.7; p < 0.001), carried HRR pathway mutations and/or BRCA1 methylation [87].
In 2021, Patsouris et al. published a phase II trial that included 42 patients, 40 of whom received at least one dose of rucaparib [113]. The study assessed the efficacy of rucaparib in HER2-negative metastatic BC with either a high genome-wide LOH score or somatic BRCA mutation [113]. The study was powered to detect a 20% clinical benefit rate [113]. The primary endpoint was not reached, with a clinical benefit rate of 13.5% [113]. Two high-LOH patients, without somatic BRCA mutation, presented a complete and durable response (the duration of response was 12 and 28.5 months in each patient) [113]. Whole-genome analysis was performed on 24 samples, including five patients who presented a clinical benefit from rucaparib [113]. HRDetect was associated with response to rucaparib, although without reaching statistical significance (median HRDetect responders vs. non-responders: 0.465 vs. 0.040, p > 0.2) [113]. Another phase II trial investigating rucaparib in untreated TNBC demonstrated that only 12% of patients had decreased Ki67 with treatment (primary endpoint) [114]. In secondary endpoint analyses, HRD was identified in 69% of TNBC patients with the mutational-signature-based HRDetect assay and confirmed by impaired RAD51 foci formation [114]. Following rucaparib treatment, there was no association between HRDetect and a Ki67 change, but circulating tumor DNA was more suppressed in patients with the HRDetect signature [114]. This data suggest that a small subset of patients with high genome-wide LOH scores and without gBRCAm could derive benefit from PARPi [113,114].

6. Discussion

PARPi have revolutionized the therapeutic landscape of BRCA-related BC. Many PARPi are still being investigated. In addition to the FDA-approved drugs olaparib and talazoparib, niraparib has shown some activity in BRCA carriers with BC on the BRAVO study and is being studied in different combinations [115]. However, the efficacy of olaparib and talazoparib have not been replicated by other contenders. Phase I clinical trials have demonstrated olaparib and talazoparib to be well-tolerated with a relatively similar side-effect profile. Olaparib is administered twice daily, while talazoparib is administered once daily. Anemia of any grade is one of the most common AEs reported with both olaparib and talazoparib. While olaparib is more commonly associated with nausea, vomiting, and fatigue, talazoparib has higher rates of cytopenia. For BRCA carriers with advanced HER2-negative BC, phase III clinical trials have demonstrated improved tolerability and superior efficacy of PARPi monotherapy in comparison to standard chemotherapy [11,12]. For BRCA carriers with early HER2-negative BC at high risk for recurrence, adjuvant olaparib was shown to significantly improve the invasive disease-free survival and OS [10,89,116]. Clinical benefits were demonstrated in all BRCA carrier patients with TNBC, those with hormone-receptor-positive disease, and patients who received previous platinum-based chemotherapy.
Selecting an adjuvant regimen for BRCA carriers with TNBC who do not achieve pCR and are therefore at high risk for relapse, remains a current clinical challenge. The results of three clinical trials (i.e., CREATE-X, OlympiA, and KEYNOTE-522) need to be considered [10,117,118]. The CREATE-X trial assigned HER2-negative BC patients with residual illness after neoadjuvant therapy (roughly one-third of whom had TNBC) to either eight cycles of adjuvant capecitabine or no additional chemotherapy. The five-year disease-free survival (74% vs. 68%; HR 0.70, 95% CI 0.53–0.92; p < 0.02) and OS (89% vs. 84%; HR for death 0.59, 95% CI 0.39–0.90; p < 0.02) were greater in capecitabine patients. Capecitabine’s improvement in disease-free survival was attributed to better outcomes among TNBC patients, according to subgroup analyses (70% vs. 56%; HR 0.58, 95% CI 0.39–0.87) [118]. Patients with stage II or III TNBC receiving neoadjuvant therapy were randomized to receive pembrolizumab or placebo every three weeks during neoadjuvant chemotherapy and for another nine cycles (27 weeks) after surgery in the KEYNOTE-522 trial. Pembrolizumab increased the pCR rate from 51% to 65%, regardless of the presence or absence of PD-L1 expression [117]. Finally, the OlympiA trial found that adjuvant olaparib improved three-year disease-free survival from 77% to 86% in BRCA carriers with early-stage, high-risk HER2-negative BC compared to placebo, and led to a significant improvement in OS (HR, 0.68; 98.5% CI 0.47–0.97; p < 0.01) [10].
The clinical benefits of sequencing or combining olaparib with other treatments such as pembrolizumab or capecitabine for the adjuvant therapy of patients with TNBC and gBRCAm is uncertain. Olaparib has been evaluated in combination with the checkpoint inhibitor durvalumab, and concurrent therapy was found to be safe and effective. However, safety data on the use of olaparib concurrently with other drugs such as temozolomide, pembrolizumab, and capecitabine are limited. Ongoing clinical trials will evaluate the combination therapy of olaparib/pembrolizumab (NCT04191135, NCT05174832, NCT03025035, NCT05203445, NCT04683679, and NCT05033756) and olaparib/temozolomide (NCT05128734) in patients with BC. The combination of olaparib/capecitabine is yet to be investigated.
Conversely, other PARPi were studied in combination with either pembrolizumab or temozolomide. Niraparib and pembrolizumab were examined in 55 patients with advanced TNBC, regardless of BRCAm status or PD-L1 expression, by Vinayak et al. An objective response was observed in ten patients (18% (five complete responses and five partial responses)). Anemia (ten—18%), thrombocytopenia (eight—15%), and fatigue (four— 7%) were the most common treatment-related AEs of grade 3 or above. Immune-related AEs were reported in eight individuals (15%), two of whom had grade 3 AEs (4%). There were no new safety signals identified [119]. For temozolomide, two studies had shown that the combination of a veliparib with temozolomide is safe without excessive toxicity [120,121]. Due to the varied potencies of different PARPi and varying myelosuppressive potential, safety results on veliparib combined with chemotherapy cannot be generalized to other PARPi.
A few clinical trials have now demonstrated the potential efficacy of PARPi beyond BRCA carriers. While the study by Gelmon et al. did not show responses in heavily pretreated patients in the metastatic setting [83], Eikesdal et al. showed a high response rate in treatment-naïve and unselected TNBC patients to olaparib monotherapy in the neoadjuvant setting [87]. In the phase II trial TBCRC-048, Tung et al. demonstrated high rates of response in patients with somatic BRCA mutation (ORR 50%) and germline PALB2 mutations (ORR 82%) [122]. Confirmatory expansion cohorts of this study are currently enrolling patients, and results are awaited. Future analyses of data from TBCRC-048 may shed light on the biomarkers of PARPi response [122]. No responses were observed with ATM or CHEK2 mutations alone [122]. Additionally, Batalini et al. showed that alpelisib and olaparib can lead to meaningful responses in heavily pre-treated patient populations [78], hence confirming the results of preclinical data that PI3Ki can render tumors sensitive to PARPi [123].
During treatment with PARPi, including olaparib and talazoparib, the complete blood count should be monitored with differential at baseline and monthly thereafter, or as clinically indicated with increasing frequency to weekly until recovery for prolonged hematologic toxicity [14,17]. Talazoparib and olaparib package inserts also require the monitoring of renal function without specifying the frequency of monitoring [14,17]. Since the dose modification of olaparib and talazoparib for renal function is required, the baseline assessment of renal function is necessary. There are no specific requirements for monitoring complete metabolic panel for either PARPi agents; however, a baseline assessment should be considered at minimum with an increase in monitoring during therapy if indicated, especially with PARPi agents that are associated with transaminitis.
As a biomarker, Sig3 is advantageous to other proposed HRD biomarkers because it leverages clinical sequencing that is already routine—gene panel sequencing—without the need for an additional assay or sequencing technology [112,124]. Sig3 captures the different mechanisms associated with underlying HRD in BC, including the biallelic inactivation of BRCA1/2, germline nonsense and frameshift variants in PALB2, missense BRCA1/2 variants known to impair HRR pathway, and the epigenetic silencing of RAD51C and BRCA1 by promoter methylation [125]. Accordingly, Batalini et al. demonstrated that Sig3 had an overall better performance than GIS for identify olaparib responders among BC patients [112]. However, prospective data are necessary to validate Sig3 as a useful biomarker.

7. Conclusions

PARPi monotherapy—olaparib and talazoparib—are approved for BRCA carriers with advanced or metastatic HER2-negative BC. Olaparib is approved in the adjuvant setting for BRCA carriers at a high risk of relapse [10]. While BRCA carriers constitute a minority of patients with BC, there is mounting evidence that PARPi could also benefit more patients [78,87,122]. The identification of a biomarker of response to PARPi remains a critical goal.

Author Contributions

Framework conception and original draft preparation: M.C.S.M. and F.B.; supervision and writing review: F.R., L.M., B.E., and F.B.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AEsadverse events
AMLacute myeloid leukemia
AUCarea under the receiver operating characteristic curve
BCbreast cancer
CIconfidence interval
Cmaxpeak serum concentration
CPS + EGclinical and pathological stage + estrogen receptor status and histological grade
CrClcreatinine clearance
gBRCAmgermline BRCA mutation
GISgenomic instability score
HER2human epidermal growth factor receptor 2
HRhazard ratio
HRDhomologous recombination repair deficiency
HRRhomologous recombination repair
LOHloss of heterozygosity
MDSmyelodysplastic syndrome
ORRobjective response rate
OSoverall survival
PARPpoly(adenosine diphosphate (ADP)–ribose) polymerase
PARPipoly(adenosine diphosphate (ADP)–ribose) polymerase inhibitors
pCRpathological complete response
PFSprogression-free survival
PI3Kphosphatidylinositol 3-kinase
PI3Kiphosphatidylinositol 3-kinase inhibitors
Sig3mutational signature 3
TNBCtriple-negative breast cancer

References

  1. Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.J.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434, 917–921. [Google Scholar] [CrossRef] [PubMed]
  2. Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913–917. [Google Scholar] [CrossRef] [PubMed]
  3. Ashworth, A. A synthetic lethal therapeutic approach: Poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 2008, 26, 3785–3790. [Google Scholar] [CrossRef] [PubMed]
  4. Murai, J.; Huang, S.-Y.N.; Das, B.B.; Renaud, A.; Zhang, Y.; Doroshow, J.H.; Ji, J.; Takeda, S.; Pommier, Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012, 72, 5588–5599. [Google Scholar] [CrossRef]
  5. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70. [Google Scholar] [CrossRef]
  6. Buys, S.S.; Sandbach, J.F.; Gammon, A.; Patel, G.; Kidd, J.; Brown, K.L.; Ms, L.S.; Saam, J.; Lancaster, J.; Daly, M.B. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017, 123, 1721–1730. [Google Scholar] [CrossRef]
  7. Dorling, L.; Carvalho, S.; Allen, J.; González-Neira, A.; Luccarini, C.; Wahlström, C.; Pooley, K.A.; Parsons, M.T.; Fortuno, C.; Wang, Q.; et al. Breast Cancer Risk Genes—Association Analysis in More than 113,000 Women. N. Engl. J. Med. 2021, 384, 428–439. [Google Scholar] [CrossRef]
  8. Hu, C.; Hart, S.N.; Gnanaolivu, R.; Huang, H.; Lee, K.Y.; Na, J.; Gao, C.; Lilyquist, J.; Yadav, S.; Boddicker, N.J.; et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N. Engl. J. Med. 2021, 384, 440–451. [Google Scholar] [CrossRef]
  9. Landrum, M.J.; Lee, J.M.; Benson, M.; Brown, G.; Chao, C.; Chitipiralla, S.; Gu, B.; Hart, J.; Hoffman, D.; Hoover, J.; et al. ClinVar: Public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016, 44, D862–D868. [Google Scholar] [CrossRef]
  10. Tutt, A.N.; Garber, J.E.; Kaufman, B.; Viale, G.; Fumagalli, D.; Rastogi, P.; Gelber, R.D.; de Azambuja, E.; Fielding, A.; Balmaña, J.; et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N. Engl. J. Med. 2021, 384, 2394–2405. [Google Scholar] [CrossRef]
  11. Litton, J.K.; Rugo, H.S.; Ettl, J.; Hurvitz, S.A.; Gonçalves, A.; Lee, K.-H.; Fehrenbacher, L.; Yerushalmi, R.; Mina, L.A.; Martin, M.; et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N. Engl. J. Med. 2018, 379, 753–763. [Google Scholar] [CrossRef] [PubMed]
  12. Robson, M.; Im, S.A.; Senkus, E.; Xu, B.; Domchek, S.M.; Masuda, N.; Delaloge, S.; Li, W.; Tung, N.; Armstrong, A.; et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med. 2017, 377, 523–533. [Google Scholar] [CrossRef] [PubMed]
  13. Moore, K.; Colombo, N.; Scambia, G.; Kim, B.-G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; Sonke, G.S.; et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2018, 379, 2495–2505. [Google Scholar] [CrossRef] [PubMed]
  14. FDA Label for Olaparib. 2021. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf (accessed on 21 December 2021).
  15. FDA Label for Rucaparib. 2021. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s004lbl.pdf (accessed on 21 December 2021).
  16. FDA Label for Niraparib. 2021. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf (accessed on 21 December 2021).
  17. FDA Label for Talazoparib. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf (accessed on 21 December 2021).
  18. Ray-Coquard, I.; Pautier, P.; Pignata, S.; Pérol, D.; González-Martín, A.; Berger, R.; Fujiwara, K.; Vergote, I.; Colombo, N.; Mäenpää, J.; et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2416–2428. [Google Scholar] [CrossRef] [PubMed]
  19. Pujade-Lauraine, E.; Ledermann, J.A.; Selle, F.; Gebski, V.; Penson, R.T.; Oza, A.M.; Korach, J.; Huzarski, T.; Poveda, A.; Pignata, S.; et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1274–1284. [Google Scholar] [CrossRef]
  20. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 2012, 366, 1382–1392. [Google Scholar] [CrossRef] [PubMed]
  21. Kaufman, B.; Shapira-Frommer, R.; Schmutzler, R.K.; Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; Hubert, A.; et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 2015, 33, 244–250. [Google Scholar] [CrossRef] [PubMed]
  22. Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.-O.; Hochhauser, D.; Arnold, D.; Oh, D.-Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 381, 317–327. [Google Scholar] [CrossRef]
  23. De Bono, J.; Mateo, J.; Fizazi, K.; Saad, F.; Shore, N.; Sandhu, S.; Chi, K.N.; Sartor, O.; Agarwal, N.; Olmos, D.; et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2020, 382, 2091–2102. [Google Scholar] [CrossRef]
  24. Ledermann, J.A.; Oza, A.M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Colombo, N.; Weberpals, J.I.; Clamp, A.R.; Scambia, G.; et al. Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): Post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020, 21, 710–722. [Google Scholar] [CrossRef]
  25. Oza, A.M.; Tinker, A.V.; Oaknin, A.; Shapira-Frommer, R.; McNeish, I.A.; Swisher, E.M.; Ray-Coquard, I.; Bell-McGuinn, K.; Coleman, R.L.; O’Malley, D.M.; et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecol. Oncol. 2017, 147, 267–275. [Google Scholar] [CrossRef] [PubMed]
  26. Abida, W.; Patnaik, A.; Campbell, D.; Shapiro, J.; Bryce, A.H.; McDermott, R.; Sautois, B.; Vogelzang, N.J.; Bambury, R.M.; Voog, E.; et al. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J. Clin. Oncol. 2020, 38, 3763–3772. [Google Scholar] [CrossRef] [PubMed]
  27. González-Martín, A.; Pothuri, B.; Vergote, I.; DePont Christensen, R.; Graybill, W.; Mirza, M.R.; McCormick, C.; Lorusso, D.; Hoskins, P.; Freyer, G.; et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2391–2402. [Google Scholar] [CrossRef]
  28. Mirza, M.R.; Monk, B.J.; Herrstedt, J.; Oza, A.M.; Mahner, S.; Redondo, A.; Fabbro, M.; Ledermann, J.A.; Lorusso, D.; Vergote, I.; et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N. Engl. J. Med. 2016, 375, 2154–2164. [Google Scholar] [CrossRef] [PubMed]
  29. Moore, K.N.; Secord, A.A.; Geller, M.A.; Miller, D.S.; Cloven, N.; Fleming, G.F.; Wahner Hendrickson, A.E.; Azodi, M.; DiSilvestro, P.; Oza, A.M.; et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019, 20, 636–648. [Google Scholar] [CrossRef]
  30. Drew, Y.; Ledermann, J.; Hall, G.; Rea, D.; Glasspool, R.; Highley, M.; Jayson, G.; Sludden, J.; Murray, J.; Jamieson, D.; et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br. J. Cancer 2016, 114, 723–730. [Google Scholar] [CrossRef]
  31. Murai, J.; Huang, S.-Y.N.; Renaud, A.; Zhang, Y.; Ji, J.; Takeda, S.; Morris, J.; Teicher, B.; Doroshow, J.H.; Pommier, Y. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol. Cancer Ther. 2014, 13, 433–443. [Google Scholar] [CrossRef]
  32. National Center for Biotechnology Information. PubChem Compound Summary for CID 23725625, Olaparib. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Olaparib (accessed on 18 August 2022).
  33. Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 2009, 361, 123–134. [Google Scholar] [CrossRef]
  34. Yamamoto, N.; Nokihara, H.; Yamada, Y.; Goto, Y.; Tanioka, M.; Shibata, T.; Yamada, K.; Asahina, H.; Kawata, T.; Shi, X.; et al. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci. 2012, 103, 504–509. [Google Scholar] [CrossRef]
  35. Bundred, N.; Gardovskis, J.; Jaskiewicz, J.; Eglitis, J.; Paramonov, V.; McCormack, P.; Swaisland, H.; Cavallin, M.; Parry, T.; Carmichael, J.; et al. Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: A phase I multicentre trial in patients scheduled for elective breast cancer surgery. Investig. New Drugs 2013, 31, 949–958. [Google Scholar] [CrossRef]
  36. Yonemori, K.; Tamura, K.; Kodaira, M.; Fujikawa, K.; Sagawa, T.; Esaki, T.; Shirakawa, T.; Hirai, F.; Yokoi, Y.; Kawata, T.; et al. Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Cancer Chemother. Pharmacol. 2016, 78, 525–531. [Google Scholar] [CrossRef]
  37. Mateo, J.; Moreno, V.; Gupta, A.; Kaye, S.B.; Dean, E.; Middleton, M.R.; Friedlander, M.; Gourley, C.; Plummer, R.; Rustin, G.; et al. An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib. Target. Oncol. 2016, 11, 401–415. [Google Scholar] [CrossRef] [PubMed]
  38. Plummer, R.; Swaisland, H.; Leunen, K.; Van Herpen, C.M.L.; Jerusalem, G.; De Greve, J.; Lolkema, M.P.; Soetekouw, P.; Mau-Sørensen, M.; Nielsen, D.; et al. Olaparib tablet formulation: Effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 2015, 76, 723–729. [Google Scholar] [CrossRef] [PubMed]
  39. Rolfo, C.; Swaisland, H.; Leunen, K.; Rutten, A.; Soetekouw, P.; Slater, S.; Verheul, H.; Fielding, A.; So, K.; Bannister, W.; et al. Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors. Adv. Ther. 2015, 32, 510–522. [Google Scholar] [CrossRef] [PubMed]
  40. AstraZeneca. Available online: https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf (accessed on 19 August 2022).
  41. Dirix, L.; Swaisland, H.; Verheul, H.M.; Rottey, S.; Leunen, K.; Jerusalem, G.; Rolfo, C.; Nielsen, D.; Molife, L.R.; Kristeleit, R.; et al. Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients with Advanced Solid Tumors: Results of Two Phase I Open-label Studies. Clin. Ther. 2016, 38, 2286–2299. [Google Scholar] [CrossRef] [PubMed]
  42. LaFargue, C.J.; Dal Molin, G.Z.; Sood, A.K.; Coleman, R.L. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol. 2019, 20, e15–e28. [Google Scholar] [CrossRef]
  43. Rolfo, C.; Isambert, N.; Italiano, A.; Molife, L.R.; Schellens, J.H.; Blay, J.; Decaens, T.; Kristeleit, R.; Rosmorduc, O.; Demlova, R.; et al. Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment. Br. J. Clin. Pharmacol. 2020, 86, 1807–1818. [Google Scholar] [CrossRef]
  44. Rolfo, C.; de Vos-Geelen, J.; Isambert, N.; Molife, L.R.; Schellens, J.H.M.; De Grève, J.; Dirix, L.; Grundtvig-Sørensen, P.; Jerusalem, G.; Leunen, K.; et al. Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment. Clin. Pharmacokinet. 2019, 58, 1165–1174. [Google Scholar] [CrossRef]
  45. Zibetti Dal Molin, G.; Westin, S.N.; Msaouel, P.; Gomes, L.M.; Dickens, A.; Coleman, R.L. Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors. Int. J. Gynecol. Cancer 2020, 30, 89–93. [Google Scholar] [CrossRef]
  46. Bruin, M.A.C.; Korse, C.M.; van Wijnen, B.; de Jong, V.M.T.; Linn, S.C.; van Triest, B.; Rosing, H.; Beijnen, J.H.; Broek, D.V.D.; Huitema, A.D.R. A real or apparent decrease in glomerular filtration rate in patients using olaparib? Eur. J. Clin. Pharmacol. 2021, 77, 179–188. [Google Scholar] [CrossRef]
  47. Morice, P.-M.; Leary, A.; Dolladille, C.; Chrétien, B.; Poulain, L.; González-Martín, A.; Moore, K.; O’Reilly, E.M.; Ray-Coquard, I.; Alexandre, J. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: A safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Lancet Haematol. 2021, 8, e122–e134. [Google Scholar] [CrossRef]
  48. Swaisland, H.; Plummer, R.; So, K.; Garnett, S.; Bannister, W.; Fabre, M.-A.; Dota, C.; Fielding, A. Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: Results from two phase I studies. Cancer Chemother. Pharmacol. 2016, 78, 775–784. [Google Scholar] [CrossRef] [PubMed]
  49. Dean, E.; Middleton, M.R.; Pwint, T.; Swaisland, H.; Carmichael, J.; Goodege-Kunwar, P.; Ranson, M. Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br. J. Cancer 2012, 106, 468–474. [Google Scholar] [CrossRef]
  50. Liu, J.F.; Tolaney, S.M.; Birrer, M.; Fleming, G.F.; Buss, M.K.; Dahlberg, S.E.; Lee, H.; Whalen, C.; Tyburski, K.; Winer, E.; et al. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur. J. Cancer 2013, 49, 2972–2978. [Google Scholar] [CrossRef]
  51. Zimmer, A.S.; Nichols, E.; Cimino-Mathews, A.; Peer, C.; Cao, L.; Lee, M.-J.; Kohn, E.C.; Annunziata, C.M.; Lipkowitz, S.; Trepel, J.B.; et al. A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women’s cancers with biomarker analyses. J. Immunother. Cancer 2019, 7, 197. [Google Scholar] [CrossRef] [PubMed]
  52. Lee, J.-M.; Cimino-Mathews, A.; Peer, C.J.; Zimmer, A.; Lipkowitz, S.; Annunziata, C.M.; Cao, L.; Harrell, M.I.; Swisher, E.M.; Houston, N.; et al. Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women’s Cancers: A Dose-Escalation, Phase I Study. J. Clin. Oncol. 2017, 35, 2193–2202. [Google Scholar] [CrossRef] [PubMed]
  53. Dent, R.A.; Lindeman, G.J.; Clemons, M.; Wildiers, H.; Chan, A.; McCarthy, N.J.; Singer, C.F.; Lowe, E.S.; Watkins, C.L.; Carmichael, J. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res. 2013, 15, R88. [Google Scholar] [CrossRef]
  54. Yuan, P.; Shentu, J.; Xu, J.; Burke, W.; Hsu, K.; Learoyd, M.; Zhu, M.; Xu, B. Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: Results of a Phase I study in Chinese patients with advanced solid tumours. Cancer Chemother. Pharmacol. 2019, 83, 963–974. [Google Scholar] [CrossRef]
  55. Pusztai, L.; Yau, C.; Wolf, D.M.; Han, H.S.; Du, L.; Wallace, A.M.; String-Reasor, E.; Boughey, J.C.; Chien, A.J.; Elias, A.D.; et al. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell 2021, 39, 989–998.e5. [Google Scholar] [CrossRef] [PubMed]
  56. Geenen, J.J.J.; Dackus, G.M.H.E.; Schouten, P.C.; Pluim, D.; Marchetti, S.; Sonke, G.S.; Jóźwiak, K.; Huitema, A.D.R.; Beijnen, J.H.; Schellens, J.H.M.; et al. A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer. Int. J. Cancer 2021, 148, 3041–3050. [Google Scholar] [CrossRef]
  57. Lee, J.-M.; Peer, C.J.; Yu, M.; Amable, L.; Gordon, N.; Annunziata, C.M.; Houston, N.; Goey, A.K.; Sissung, T.M.; Parker, B.; et al. Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women’s Cancer. Clin. Cancer Res. 2017, 23, 1397–1406. [Google Scholar] [CrossRef] [PubMed]
  58. Lee, J.-M.; Hays, J.L.; Annunziata, C.M.; Noonan, A.M.; Minasian, L.; Zujewski, J.A.; Yu, M.; Gordon, N.; Ji, J.; Sissung, T.M.; et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J. Natl. Cancer Inst. 2014, 106, dju089. [Google Scholar] [CrossRef] [PubMed]
  59. Peer, C.J.; Lee, J.-M.; Roth, J.; Rodgers, L.; Nguyen, J.; Annunziata, C.M.; Minasian, L.; Kohn, E.C.; Figg, W.D. Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers. Cancer Chemother. Pharmacol. 2017, 80, 165–175. [Google Scholar] [CrossRef] [PubMed]
  60. Van der Noll, R.; Jager, A.; Ang, J.E.; Marchetti, S.; Mergui-Roelvink, M.W.J.; Lolkema, M.P.; de Jonge, M.J.A.; van der Biessen, D.A.; Brunetto, A.T.; Arkenau, H.-T.; et al. Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1). Investig. New Drugs 2020, 38, 1117–1128. [Google Scholar] [CrossRef] [PubMed]
  61. Van der Noll, R.; Jager, A.; Ang, J.E.; Marchetti, S.; Mergui-Roelvink, M.W.J.; de Bono, J.S.; Lolkema, M.P.; de Jonge, M.J.A.; van der Biessen, D.A.; Brunetto, A.T.; et al. Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2). Investig. New Drugs 2020, 38, 1096–1107. [Google Scholar] [CrossRef] [PubMed]
  62. Van Der Noll, R.; Marchetti, S.; Steeghs, N.; Beijnen, J.H.; Mergui-Roelvink, M.W.J.; Harms, E.; Rehorst, H.; Sonke, G.; Schellens, J.H.M. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br. J. Cancer 2015, 113, 396–402. [Google Scholar] [CrossRef] [PubMed]
  63. Lee, C.K.; Scott, C.; Lindeman, G.J.; Hamilton, A.; Lieschke, E.; Gibbs, E.; Asher, R.; Badger, H.; Paterson, R.; Macnab, L.; et al. Phase 1 trial of olaparib and oral cyclophosphamide in BRCA breast cancer, recurrent BRCA ovarian cancer, non-BRCA triple-negative breast cancer, and non-BRCA ovarian cancer. Br. J. Cancer 2019, 120, 279–285. [Google Scholar] [CrossRef]
  64. Del Conte, G.; Sessa, C.; Von Moos, R.; Viganò, L.; Digena, T.; Locatelli, A.; Gallerani, E.; Fasolo, A.; Tessari, A.; Cathomas, R.; et al. Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br. J. Cancer 2014, 111, 651–659. [Google Scholar] [CrossRef]
  65. Balmaña, J.; Tung, N.M.; Isakoff, S.J.; Graña, B.; Ryan, P.D.; Saura, C.; Lowe, E.S.; Frewer, P.; Winer, E.; Baselga, J.; et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann. Oncol. 2014, 25, 1656–1663. [Google Scholar] [CrossRef]
  66. Poveda, A.; Oaknin, A.; Romero, I.; Guerrero-Zotano, A.; Fariñas-Madrid, L.; Rodriguez-Freixinos, V.; Mallol, P.; Lopez-Reig, R.; Lopez-Guerrero, J.A. A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors. Sci. Rep. 2021, 11, 4433. [Google Scholar] [CrossRef]
  67. Domchek, S.M.; Postel-Vinay, S.; Im, S.-A.; Park, Y.H.; Delord, J.-P.; Italiano, A.; Alexandre, J.; You, B.; Bastian, S.; Krebs, M.G.; et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): An open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020, 21, 1155–1164. [Google Scholar] [CrossRef]
  68. Khan, O.A.; Gore, M.; Lorigan, P.; Stone, J.; Greystoke, A.; Burke, W.; Carmichael, J.; Watson, A.J.; McGown, G.; Thorncroft, M.; et al. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br. J. Cancer 2011, 104, 750–755. [Google Scholar] [CrossRef] [PubMed]
  69. Yonemori, K.; Shimomura, A.; Yasojima, H.; Masuda, N.; Aogi, K.; Takahashi, M.; Naito, Y.; Shimizu, S.; Nakamura, R.; Hashimoto, J.; et al. A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes. Eur. J. Cancer 2019, 109, 84–91. [Google Scholar] [CrossRef] [PubMed]
  70. Mahdi, H.; Hafez, N.; Doroshow, D.; Sohal, D.; Keedy, V.; Do, K.T.; LoRusso, P.; Jürgensmeier, J.; Avedissian, M.; Sklar, J.; et al. Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). JCO Precis. Oncol. 2021, 5, 1432–1442. [Google Scholar] [CrossRef]
  71. Konstantinopoulos, P.A.; Cheng, S.-C.; Supko, J.G.; Polak, M.; Wahner-Hendrickson, A.E.; Ivy, S.P.; Bowes, B.; Sawyer, H.; Basada, P.; Hayes, M.; et al. Combined PARP and HSP90 inhibition: Preclinical and Phase 1 evaluation in patients with advanced solid tumours. Br. J. Cancer 2022, 126, 1027–1036. [Google Scholar] [CrossRef]
  72. Do, K.T.; Kochupurakkal, B.S.; Kelland, S.; de Jonge, A.; Hedglin, J.; Powers, A.; Quinn, N.; Gannon, C.; Vuong, L.; Parmar, K.; et al. Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors. Clin. Cancer Res. 2021, 27, 4710–4716. [Google Scholar] [CrossRef]
  73. Bendell, J.; O’Reilly, E.M.; Middleton, M.R.; Chau, I.; Hochster, H.; Fielding, A.; Burke, W.; Burris, I.H. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann. Oncol. 2015, 26, 804–811. [Google Scholar] [CrossRef]
  74. Rajan, A.; Carter, C.A.; Kelly, R.J.; Gutierrez, M.; Kummar, S.; Szabo, E.; Yancey, M.A.; Ji, J.; Mannargudi, B.; Woo, S.; et al. A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin. Cancer Res. 2012, 18, 2344–2351. [Google Scholar] [CrossRef]
  75. Samol, J.; Ranson, M.; Scott, E.; Macpherson, E.; Carmichael, J.; Thomas, A.; Cassidy, J. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: A phase I study. Investig. New Drugs 2012, 30, 1493–1500. [Google Scholar] [CrossRef]
  76. Loap, P.; Loirat, D.; Berger, F.; Ricci, F.; Vincent-Salomon, A.; Ezzili, C.; Mosseri, V.; Fourquet, A.; Ezzalfani, M.; Kirova, Y. Combination of Olaparib and Radiation Therapy for Triple Negative Breast Cancer: Preliminary Results of the RADIOPARP Phase 1 Trial. Int. J. Radiat. Oncol. Biol. Phys. 2021, 109, 436–440. [Google Scholar] [CrossRef]
  77. Matulonis, U.A.; Wulf, G.M.; Barry, W.T.; Birrer, M.; Westin, S.N.; Farooq, S.; Bell-McGuinn, K.M.; Obermayer, E.; Whalen, C.; Spagnoletti, T.; et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann. Oncol. 2017, 28, 512–518. [Google Scholar] [CrossRef]
  78. Batalini, F.; Xiong, N.; Tayob, N.; Polak, M.; Eismann, J.; Cantley, L.C.; Shapiro, G.I.; Adalsteinsson, V.; Winer, E.P.; Konstantinopoulos, P.A.; et al. Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer. Clin. Cancer Res. 2022, 28, 1493–1499. [Google Scholar] [CrossRef] [PubMed]
  79. Yap, T.A.; Kristeleit, R.; Michalarea, V.; Pettitt, S.J.; Lim, J.S.; Carreira, S.; Roda, D.; Miller, R.; Riisnaes, R.; Miranda, S.; et al. Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers. Cancer Discov. 2020, 10, 1528–1543. [Google Scholar] [CrossRef]
  80. Westin, S.N.; Labrie, M.; Litton, J.K.; Blucher, A.; Fang, Y.; Vellano, C.P.; Marszalek, J.R.; Feng, N.; Ma, X.; Creason, A.; et al. Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer. Clin. Cancer Res. 2021, 27, 6354–6365. [Google Scholar] [CrossRef]
  81. Plummer, R.; Verheul, H.M.; De Vos, F.Y.F.L.; Leunen, K.; Molife, L.R.; Rolfo, C.; Grundtvig-Sørensen, P.; De Grève, J.; Rottey, S.; Jerusalem, G.; et al. Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Adv. Ther. 2018, 35, 1945–1964. [Google Scholar] [CrossRef]
  82. Tutt, A.; Robson, M.; Garber, J.E.; Domchek, S.M.; Audeh, M.W.; Weitzel, J.N.; Friedlander, M.; Arun, B.; Loman, N.; Schmutzler, R.K.; et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010, 376, 235–244. [Google Scholar] [CrossRef]
  83. Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011, 12, 852–861. [Google Scholar] [CrossRef]
  84. Robson, M.E.; Tung, N.; Conte, P.; Im, S.-A.; Senkus, E.; Xu, B.; Masuda, N.; Delaloge, S.; Li, W.; Armstrong, A.; et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol. 2019, 30, 558–566. [Google Scholar] [CrossRef] [PubMed]
  85. Robson, M.; Ruddy, K.J.; Im, S.-A.; Senkus, E.; Xu, B.; Domchek, S.M.; Masuda, N.; Li, W.; Tung, N.; Armstrong, A.; et al. Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial. Eur. J. Cancer 2019, 120, 20–30. [Google Scholar] [CrossRef]
  86. Gelmon, K.A.; Fasching, P.A.; Couch, F.J.; Balmaña, J.; Delaloge, S.; Labidi-Galy, I.; Bennett, J.; McCutcheon, S.; Walker, G.; O’Shaughnessy, J.; et al. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: Phase IIIb LUCY interim analysis. Eur. J. Cancer 2021, 152, 68–77. [Google Scholar] [CrossRef] [PubMed]
  87. Eikesdal, H.; Yndestad, S.; Elzawahry, A.; Llop-Guevara, A.; Gilje, B.; Blix, E.; Espelid, H.; Lundgren, S.; Geisler, J.; Vagstad, G.; et al. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann. Oncol. 2021, 32, 240–249. [Google Scholar] [CrossRef] [PubMed]
  88. Mittendorf, E.A.; Jeruss, J.S.; Tucker, S.L.; Kolli, A.; Newman, L.A.; Gonzalez-Angulo, A.M.; Buchholz, T.A.; Sahin, A.A.; Cormier, J.N.; Buzdar, A.U.; et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J. Clin. Oncol. 2011, 29, 1956–1962. [Google Scholar] [CrossRef] [PubMed]
  89. Tutt, A.N.J.; Garber, J.; Gelber, R.D.; Phillips, K.-A.; Eisen, A.; Johannsson, O.T.; Rastogi, P.; Cui, K.Y.; Im, S.; Yerushalmi, R.; et al. Prespecified Event-Driven Analysis of Overall Survival in the OlympiA Phase III Trial of Adjuvant Olaparib in Germline BRCA1/2 Mutation Associated Breast Cancer. In ESMO Virtual Plenary. Abstract VP1-2022; ESMO: Lugano, Switzerland, 2022. [Google Scholar]
  90. Tung, N.M.; Zakalik, D.; Somerfield, M.R.; Hereditary Breast Cancer Guideline Expert Panel. Adjuvant PARP Inhibitors in Patients with High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update. J. Clin. Oncol. 2021, 39, 2959–2961. [Google Scholar] [CrossRef] [PubMed]
  91. Kawachi, A.; Yamashita, S.; Okochi-Takada, E.; Hirakawa, A.; Tsuda, H.; Shimomura, A.; Kojima, Y.; Yonemori, K.; Fujiwara, Y.; Kinoshita, T.; et al. BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy. Breast Cancer Res. Treat. 2020, 181, 323–329. [Google Scholar] [CrossRef] [PubMed]
  92. Fasching, P.; Link, T.; Hauke, J.; Seither, F.; Jackisch, C.; Klare, P.; Schmatloch, S.; Hanusch, C.; Huober, J.; Stefek, A.; et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann. Oncol. 2021, 32, 49–57. [Google Scholar] [CrossRef]
  93. National Center for Biotechnology Information. PubChem Compound Summary for CID 135565082, Talazoparib. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/135565082 (accessed on 18 August 2022).
  94. De Bono, J.; Ramanathan, R.K.; Mina, L.; Chugh, R.; Glaspy, J.; Rafii, S.; Kaye, S.; Sachdev, J.; Heymach, J.; Smith, D.C.; et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov. 2017, 7, 620–629. [Google Scholar] [CrossRef]
  95. Naito, Y.; Kuboki, Y.; Ikeda, M.; Harano, K.; Matsubara, N.; Toyoizumi, S.; Mori, Y.; Hori, N.; Nagasawa, T.; Kogawa, T. Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: Phase 1 study. Investig. New Drugs 2021, 39, 1568–1576. [Google Scholar] [CrossRef]
  96. Yu, Y.; Chung, C.; Plotka, A.; Quinn, K.; Shi, H.; Pápai, Z.; Nguyen, L.; Wang, D. A Phase 1 Mass Balance Study of (14) C-Labeled Talazoparib in Patients with Advanced Solid Tumors. J. Clin. Pharmacol. 2019, 59, 1195–1203. [Google Scholar] [CrossRef]
  97. Durairaj, C.; Chakrabarti, J.; Ferrario, C.; Hirte, H.W.; Babu, S.; Piha-Paul, S.A.; Plotka, A.; Hoffman, J.; Shi, H.; Wang, D.D. The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors. Clin. Pharmacokinet. 2021, 60, 921–930. [Google Scholar] [CrossRef]
  98. Dhawan, M.S.; Bartelink, I.H.; Aggarwal, R.R.; Leng, J.; Zhang, J.Z.; Pawlowska, N.; Terranova-Barberio, M.; Grabowsky, J.A.; Gewitz, A.; Chien, A.J.; et al. Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors. Clin. Cancer Res. 2017, 23, 6400–6410. [Google Scholar] [CrossRef] [Green Version]
  99. Schafer, E.S.; Rau, R.; Berg, S.L.; Liu, X.; Minard, C.G.; Bishop, A.J.; Romero, J.C.; Hicks, M.J.; Nelson, M.D.; Voss, S.; et al. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children’s Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr. Blood Cancer 2020, 67, e28073. [Google Scholar] [CrossRef] [PubMed]
  100. Federico, S.M.; Pappo, A.S.; Sahr, N.; Sykes, A.; Campagne, O.; Stewart, C.F.; Clay, M.R.; Bahrami, A.; McCarville, M.B.; Kaste, S.C.; et al. A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Eur. J. Cancer 2020, 137, 204–213. [Google Scholar] [CrossRef] [PubMed]
  101. Elmeliegy, M.; Yu, Y.; Litton, J.K.; Czibere, A.; Wilson, G.G.; Tudor, I.C.; Zheng, J.; Wang, D.D. Exposure-Safety Analyses of Talazoparib in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials. J. Clin. Pharmacol. 2020, 60, 1334–1343. [Google Scholar] [CrossRef] [PubMed]
  102. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Published online 27 November 2017. Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf (accessed on 25 May 2022).
  103. Ettl, J.; Quek, R.; Lee, K.-H.; Rugo, H.; Hurvitz, S.; Gonçalves, A.; Fehrenbacher, L.; Yerushalmi, R.; Mina, L.; Martin, M.; et al. Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: Patient-reported outcomes from the EMBRACA phase III trial. Ann. Oncol. 2018, 29, 1939–1947. [Google Scholar] [CrossRef] [PubMed]
  104. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Antiemetics Version 2.2022; National Comprehensive Cancer Network: Plymouth Meeting, PA, USA, 2022. [Google Scholar]
  105. Turner, N.C.; Telli, M.L.; Rugo, H.S.; Mailliez, A.; Ettl, J.; Grischke, E.-M.; Mina, L.A.; Balmaña, J.; Fasching, P.A.; Hurvitz, S.A.; et al. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin. Cancer Res. 2019, 25, 2717–2724. [Google Scholar] [CrossRef]
  106. Hurvitz, S.; Quek, R.; Turner, N.; Telli, M.; Rugo, H.; Mailliez, A.; Ettl, J.; Grischke, E.; Mina, L.; Balmaña, J.; et al. Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: Patient-reported outcomes from the ABRAZO phase 2 trial. Eur. J. Cancer 2018, 104, 160–168. [Google Scholar] [CrossRef]
  107. Litton, J.K.; Scoggins, M.; Ramirez, D.L.; Murthy, R.K.; Whitman, G.J.; Hess, K.R.; Adrada, B.E.; Moulder, S.L.; Barcenas, C.H.; Valero, V.; et al. A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation. Ann. Oncol. 2016, 27, vi46. [Google Scholar] [CrossRef]
  108. Litton, J.K.; Scoggins, M.E.; Hess, K.R.; Adrada, B.E.; Murthy, R.K.; Damodaran, S.; DeSnyder, S.M.; Brewster, A.M.; Barcenas, C.H.; Valero, V.; et al. Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant. J. Clin. Oncol. 2020, 38, 388–394. [Google Scholar] [CrossRef]
  109. Telli, M.L.; Timms, K.M.; Reid, J.; Hennessy, B.; Mills, G.B.; Jensen, K.C.; Szallasi, Z.; Barry, W.T.; Winer, E.P.; Tung, N.M.; et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin. Cancer Res. 2016, 22, 3764–3773. [Google Scholar] [CrossRef]
  110. Mayer, E.L.; Abramson, V.; Jankowitz, R.; Falkson, C.; Marcom, P.K.; Traina, T.; Carey, L.; Rimawi, M.; Specht, J.; Miller, K.; et al. TBCRC 030: A phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: Evaluating the homologous recombination deficiency (HRD) biomarker. Ann. Oncol. 2020, 31, 1518–1525. [Google Scholar] [CrossRef]
  111. Blum, J.L.; Laird, A.D.; Litton, J.K.; Rugo, H.S.; Ettl, J.; Hurvitz, S.A.; Martin, M.; Roché, H.H.; Lee, K.-H.; Goodwin, A.; et al. Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer. Clin. Cancer Res. 2022, 28, 1383–1390. [Google Scholar] [CrossRef] [PubMed]
  112. Batalini, F.; Gulhan, D.; Mao, V.; Tran, A.; Polak, M.; Xiong, N.; Tayob, N.; Tung, N.M.; Winer, E.P.; Mayer, E.L.; et al. Mutational signature 3 detected from clinical panel sequencing is associated with responses to olaparib in breast and ovarian cancers. Clin. Cancer Res. 2022, CCR-22-0749, (Online ahead of print). [Google Scholar] [CrossRef] [PubMed]
  113. Patsouris, A.; Diop, K.; Tredan, O.; Nenciu, D.; Gonçalves, A.; Arnedos, M.; Sablin, M.-P.; Jézéquel, P.; Jimenez, M.; Droin, N.; et al. Rucaparib in patients presenting a metastatic breast cancer with homologous recombination deficiency, without germline BRCA1/2 mutation. Eur. J. Cancer 2021, 159, 283–295. [Google Scholar] [CrossRef] [PubMed]
  114. Chopra, N.; Tovey, H.; Pearson, A.; Cutts, R.; Toms, C.; Proszek, P.; Hubank, M.; Dowsett, M.; Dodson, A.; Daley, F.; et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat. Commun. 2020, 11, 2662. [Google Scholar] [CrossRef] [PubMed]
  115. Turner, N.C.; Balmaña, J.; Poncet, C.; Goulioti, T.; Tryfonidis, K.; Honkoop, A.H.; Zoppoli, G.; Razis, E.; Johannsson, O.T.; Colleoni, M.; et al. Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: The EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. Clin. Cancer Res. 2021, 27, 5482–5491. [Google Scholar] [CrossRef]
  116. Perez-Fidalgo, J.; Cortés, A.; Guerra, E.; García, Y.; Iglesias, M.; Sarmiento, U.B.; García, E.C.; Sánchez, L.M.; Santaballa, A.; Oaknin, A.; et al. Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: A GEICO phase II trial (ROLANDO study). ESMO Open 2021, 6, 100212. [Google Scholar] [CrossRef]
  117. Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; Harbeck, N.; et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2020, 382, 810–821. [Google Scholar] [CrossRef]
  118. Masuda, N.; Lee, S.-J.; Ohtani, S.; Im, Y.-H.; Lee, E.-S.; Yokota, I.; Kuroi, K.; Im, S.-A.; Park, B.-W.; Kim, S.-B.; et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N. Engl. J. Med. 2017, 376, 2147–2159. [Google Scholar] [CrossRef]
  119. Vinayak, S.; Tolaney, S.M.; Schwartzberg, L.; Mita, M.; McCann, G.; Tan, A.R.; Wahner-Hendrickson, A.E.; Forero, A.; Anders, C.; Wulf, G.M.; et al. Open-label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol. 2019, 5, 1132–1140. [Google Scholar] [CrossRef]
  120. Han, H.S.; Diéras, V.; Robson, M.; Palácová, M.; Marcom, P.K.; Jager, A.; Bondarenko, I.; Citrin, D.; Campone, M.; Telli, M.L.; et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: Randomized phase II study. Ann. Oncol. 2018, 29, 154–161. [Google Scholar] [CrossRef]
  121. Xu, J.; Keenan, T.E.; Overmoyer, B.; Tung, N.M.; Gelman, R.S.; Habin, K.; Garber, J.E.; Ellisen, L.W.; Winer, E.P.; Goss, P.E.; et al. Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations. Breast Cancer Res. Treat. 2021, 189, 641–651. [Google Scholar] [CrossRef] [PubMed]
  122. Tung, N.M.; Robson, M.E.; Ventz, S.; Santa-Maria, C.A.; Nanda, R.; Marcom, P.K.; Shah, P.D.; Ballinger, T.J.; Yang, E.S.; Vinayak, S.; et al. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J. Clin. Oncol. 2020, 38, 4274–4282. [Google Scholar] [CrossRef] [PubMed]
  123. Juvekar, A.; Burga, L.N.; Hu, H.; Lunsford, E.P.; Ibrahim, Y.H.; Balmaña, J.; Rajendran, A.; Papa, A.; Spencer, K.; Lyssiotis, C.A.; et al. Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer. Cancer Discov. 2012, 2, 1048–1063. [Google Scholar] [CrossRef] [PubMed]
  124. Gulhan, D.C.; Lee, J.J.-K.; Melloni, G.E.M.; Cortés-Ciriano, I.; Park, P.J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat. Genet. 2019, 51, 912–919. [Google Scholar] [CrossRef] [PubMed]
  125. Polak, P.; Kim, J.; Braunstein, L.Z.; Karlic, R.; Haradhavala, N.J.; Tiao, G.; Rosebrock, D.; Livitz, D.; Kübler, K.; Mouw, K.W.; et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 2017, 49, 1476–1486. [Google Scholar] [CrossRef]
Cancers 14 04332 g001 550
Figure 1. A synthetic lethality therapeutic approach: poly(ADP) ribose polymerase inhibitors (PARPi) for the treatment of cancers with a deficient homologous recombination repair (HRR) pathway. Neither PARPi nor HRR deficiency (HRD) alone is lethal, but the inadequate repair of double-strand breaks found in HRR-deficient cells renders them sensitive to PARP inhibition.
Figure 1. A synthetic lethality therapeutic approach: poly(ADP) ribose polymerase inhibitors (PARPi) for the treatment of cancers with a deficient homologous recombination repair (HRR) pathway. Neither PARPi nor HRR deficiency (HRD) alone is lethal, but the inadequate repair of double-strand breaks found in HRR-deficient cells renders them sensitive to PARP inhibition.
Cancers 14 04332 g001
Cancers 14 04332 g002 550
Figure 2. Search strategy. On 29 April 2022, the following PubMed search was performed: “breast” AND “Olaparib OR AZD2281 OR Talazoparib OR BMN673”. The references were also scanned for eligible studies. There were 177 results. Among them, 106 studies were excluded, as 91 cited the word breast in the body of the text but were not about breast cancer, 6 were not experimental studies, five were subanalyses of included studies, 3 were duplicated studies, and 1 was an experiment that included neither olaparib nor talazoparib. Accordingly, 71 studies were included, with two additional studies from the references.
Figure 2. Search strategy. On 29 April 2022, the following PubMed search was performed: “breast” AND “Olaparib OR AZD2281 OR Talazoparib OR BMN673”. The references were also scanned for eligible studies. There were 177 results. Among them, 106 studies were excluded, as 91 cited the word breast in the body of the text but were not about breast cancer, 6 were not experimental studies, five were subanalyses of included studies, 3 were duplicated studies, and 1 was an experiment that included neither olaparib nor talazoparib. Accordingly, 71 studies were included, with two additional studies from the references.
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Table
Table 1. Associations between pathogenic variants in established breast-cancer-predisposition genes and risk of breast cancer.
Table 1. Associations between pathogenic variants in established breast-cancer-predisposition genes and risk of breast cancer.
Pathogenic VariantOdds Ratio (95% CI)p-Value
BRCA17.62 (5.33–11.27)<0.001
BRCA25.23 (4.09–6.77)<0.001
PALB23.83 (2.68–5.63)<0.001
ATM1.82 (1.46–2.27)<0.001
CHEK22.47 (2.02–3.05)<0.001
Adapted from reference [8], with loss-of-function variants and variants identified as “pathogenic” or “likely pathogenic” in the ClinVar [9] database.
Table
Table 2. FDA indications for poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) in a variety of cancers.
Table 2. FDA indications for poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) in a variety of cancers.
DrugIndications [14,15,16,17]BiomarkerMain Trial
OlaparibAdvanced epithelial ovarian *BRCA1/2SOLO-1 [13] (2018)
Advanced epithelial ovarian *BRCA1/2, or GISPAOLA-1 [18] (2020)
Recurrent epithelial ovarian *XSOLO-2 [19] (2017), Study 19 [20] (2017)
Advanced ovariangBRCA1/2NCT01078662 [21] (2014)
Metastatic breast: HER2-negativegBRCA1/2OlympiAD [12] (2018)
Metastatic pancreatic adenocarcinomagBRCA1/2POLO [22] (2019)
Metastatic prostateATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51, RAD54LPROfound [23] (2020)
RucaparibRecurrent epithelial ovarian *XARIEL3 [24] (2018)
Epithelial ovarian *BRCA1/2Study 10 and ARIEL2 [25] (2016)
Metastatic prostateBRCA1/2TRITON2 [26] (2020)
NiraparibAdvanced epithelial ovarian *XPRIMA [27] (2020)
Recurrent epithelial ovarian *XNOVA [28] (2017)
Advanced ovarian *BRCA1/2 or GISQUADRA [29] (2019)
TalazoparibMetastatic/advanced breast: HER2-negativegBRCA1/2EMBRACA [11] (2018)
* Additionally, fallopian tube or primary peritoneal; gBRCAm: germline BRCA mutation; HER2: human epidermal growth factor receptor 2; GIS: genomic instability score. Indications for use in breast cancer patients are bolded.
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Menezes, M.C.S.; Raheem, F.; Mina, L.; Ernst, B.; Batalini, F. PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond. Cancers 2022, 14, 4332. https://doi.org/10.3390/cancers14174332

AMA Style

Menezes MCS, Raheem F, Mina L, Ernst B, Batalini F. PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond. Cancers. 2022; 14(17):4332. https://doi.org/10.3390/cancers14174332

Chicago/Turabian Style

Menezes, Maria Clara Saad, Farah Raheem, Lida Mina, Brenda Ernst, and Felipe Batalini. 2022. "PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond" Cancers 14, no. 17: 4332. https://doi.org/10.3390/cancers14174332

APA Style

Menezes, M. C. S., Raheem, F., Mina, L., Ernst, B., & Batalini, F. (2022). PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond. Cancers, 14(17), 4332. https://doi.org/10.3390/cancers14174332

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