ABSTRACT PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic

lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%–19% of patients with primary prostate cancer have inactivated DNA repair genes, with

a notably higher proportion of 23%–27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to

PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these

access to this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS TARGETING SIGNALING PATHWAYS IN PROSTATE CANCER: MECHANISMS AND CLINICAL TRIALS Article Open

access 24 June 2022 EFFECTIVENESS AND DURABILITY OF BENEFIT OF MTOR INHIBITORS IN A REAL-WORLD COHORT OF PATIENTS WITH METASTATIC PROSTATE CANCER AND PI3K PATHWAY ALTERATIONS Article 19

November 2022 TOPOISOMERASE II ALPHA INHIBITION CAN OVERCOME TAXANE-RESISTANT PROSTATE CANCER THROUGH DNA REPAIR PATHWAYS Article Open access 15 November 2021 INTRODUCTION Prostate cancer is

the most common malignancy and the second most common cause of death among so-called “male cancers.” According to the most recent estimates from the American Cancer Society, there will be

~191,930 new cases of prostate cancer (21% of new cases of male cancers) and 33,330 associated deaths (10% of deaths from male cancers) in the United States in 2020 [1]. Although it is

possible to cure prostate cancer in patients with early-stage disease, patients with metastatic disease have poor outcomes. The overall survival of patients with metastatic prostate cancer

has not improved over the past 20 years [2]. Since its efficacy was first reported in 1941, androgen deprivation therapy (ADT) has remained the initial treatment for metastatic prostate

cancer [3]. However, patients will inevitably progress to a condition that adapts to castration with continuous androgen deprivation, which is termed castration-resistant prostate cancer

(CRPC). Although some new therapies have emerged, such as sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, they have conferred only modest benefits to the

overall survival [4,5,6,7]. Meanwhile, PARP inhibitors have shown significant benefits in patients with ovarian cancer with _BRCA1/2_ mutations [8, 9]. In addition, systematic genomic

analyzes revealed the enrichment of mutations in the DNA repair pathway in metastatic castration-resistant prostate cancer (mCRPC), implying that patients with mCRPC were vulnerable to PARP

inhibitors [10]. PARPs are involved in DNA repair and transcriptional regulation by controlling the pathways needed for prostate malignancy [11]. Moreover, PARP-1 enzymatic activity is

elevated during prostate cancer progression and is associated with poor outcomes [12]. Therefore, PARPs are potential targets to treat prostate cancer. PARP inhibitors are a group of

inhibitors targeting poly(ADP-ribose) polymerases (PARP1 and PARP2). These drugs reduce the enzymatic activity of PARP and induce double-strand breaks (DSBs) by DNA trapping. The action of

PARP inhibitors could induce synthetic lethality in patients with homologous recombination deficiency (HRD). The first PARP inhibitor to be granted a breakthrough therapy designation by the

food and drug administration (FDA) for patients with mCRPC was olaparib [10]. Subsequently, other PARP inhibitors—rucaparib and niraparib—were granted breakthrough therapy designation by the

FDA for patients with mCRPC with _BRCA1/2_ mutations in 2018 and 2019, respectively [13, 14]. In addition, to overcome the limitations of the application of PARP inhibitors in patients with

HRD, the combination of specific agents offers a new therapeutic strategy. Notably, the combination of abiraterone and olaparib was reported to prolong progression-free survival (PFS),

regardless of the mutation status of homologous recombination (HR) repair, in patients with mCRPC [15]. Abiraterone and olaparib mutually increase the efficacy of each other. Although the

efficacy of PARP inhibitors in patients with mCRPC has been reported in various studies, the population of patients with prostate cancer who benefit from PARP inhibitors is limited by the

lack of biomarkers for the identification of sensitive patients and the intrinsic resistance of the remaining patients. The main focus of this review is to summarize two options used to

widen the applicability of PARP inhibitors: (1) biomarkers, other than _BRCA1/2_ mutations, to predict response; and (2) synergistic combinations of drugs to induce HRD. The studies

discussed are still in the preclinical and clinical stages; hence, they have the potential to facilitate the wider use of PARP inhibitors. MECHANISM OF PARP INHIBITION PARPs are a family of

proteins that participate in the DNA damage response (DDR), genomic stability, and programmed cell death and include PARP1 (the more important protein) and PARP2 [16]. PARP1 and PARP2 are

both molecular sensors and signal transducers of DNA breaks [17]. When damage occurs in a DNA strand, it is detected by PARP1 binding. After binding to single-strand breaks (SSBs), PARP1

exerts catalytic activity with the cofactor β-NAD+ and induces PARylation of substrate proteins, which promotes the recruitment of DNA repair effectors. Subsequently, DNA repair effectors

mediate DNA repair after PARP1 is released from DNA by autoPARylation. Meanwhile, PARP1 returns to a catalytically inactivated state [18,19,20]. The main function of PARP inhibitors is to

bind the catalytic domain of PARP, which blocks a PARP protein from the SSB site and reduces its catalytic activity. In addition, PARP inhibitors hinder the process of DNA repair and finally

induce toxic DSBs [21]. Although the DSBs induced by PARP inhibitors could be repaired by competent DSB repair capacity in HR-proficient cells, in HR-deficient cells, DSBs induced by PARP

inhibitors remain unrepaired and eventually cause programmed cell death. This process, a typical example of synthetic lethality, is the rationale for the antitumor effect of PARP inhibitors

[22, 23]. In addition, as a ubiquitously expressed nuclear enzyme, PARP1 is involved in many biological functions, such as genomic stability, programmed cell death, transcriptional

regulation, and chromatin structure modulation [17, 24,25,26]. The role of PARP1 in genomic stability is summarized in Fig. 1a. The increased genomic instability caused by the inhibition of

PARP1 promotes the cytotoxicity of PARP inhibitors. Furthermore, there is an increasing body of evidence to support the role of PARP1 in the function of the androgen receptor (AR) and

erythroblast transformation-specific (ETS) proteins [24, 27]. Therefore, the anticancer effects of PARP inhibitors are also mediated by impairing the functions of AR and ETS. A schematic

overview of the antitumor effect induced by PARP inhibitors is shown in Fig. 1. CLINICAL TRIALS OF PARP INHIBITORS IN PROSTATE CANCER The efficacy of PARP inhibitors in prostate cancer was

first reported in the phase I clinical trial of olaparib [9]. This trial included three patients with CRPC and the patient with a _BRCA2_ mutation showed a 50% decline in the level of

prostate-specific antigen (PSA) and a decrease in bone metastases. Furthermore, the efficacy of PARP inhibitors in prostate cancer was assessed in a landmark trial named TOPARP-A (trial of

olaparib in patients with advanced castration-resistant prostate cancer), which resulted in the breakthrough therapy designation by the FDA for the treatment of patients with mCRPC with

_BRCA1/2_ or _ATM_ mutations [10]. TOPARP-A was a phase II trial that included 49 evaluable patients with CRPC. In the results of this trial, a 33% (16/49) overall response rate (RR) in

unselected patients with CRPC was reported; remarkably, 88% (14/16) of responders were biomarker-positive. In contrast, only 6% (2/33) of biomarker-negative patients responded to olaparib.

Among the 16 biomarker-positive patients, all patients with _BRCA1/2_ germline or somatic alterations responded to olaparib; this accounted for the major proportion of biomarker-positive

patients who exhibited a response (8 of 14). This suggested that _BRCA1/2_ mutants were stronger biomarkers for patient stratification. In addition, 4 of 5 patients with _ATM_ alterations

were sensitive to olaparib treatment, and patients with alterations in _FANCA_, _CHEK2_, _PALB2_, _HDAC2_, and other HR-related genes also responded to olaparib. To validate the biomarkers

identified in TOPARP-A, the TOPARP-B study enrolled 98 patients with DDR gene alterations to receive treatment with olaparib [28]. Approximately 83.3% (25/30) of the patients with _BRCA1/2_

mutations showed a composite overall response, which confirmed the superior predictive power of _BRCA1/2_ mutations. The response was also identified in other subpopulations, such as

patients with _PALB2_ alterations. However, in contrast to the results of TOPARP-A, only 10.5% (2/19) of the patients with _ATM_ aberrations achieved a RECIST or PSA response in TOPARP-B

(enrolled 98 patients), and none of the five patients with _ATM_ aberrations in TRITON2 (enrolled 85 patients) achieved a clinical response [13, 28]. This suggested that the prediction power

of _ATM_ alterations alone was not sufficient to identify a population of patients who would benefit from this treatment. Furthermore, PARP inhibitors have been studied in phase III trials,

including PROfound and TRITON3, as first-line choices in comparison with AR inhibitors such as abiraterone acetate or enzalutamide. Recent results from PROfound showed significantly better

outcomes in patients treated with olaparib than in patients treated with either enzalutamide or abiraterone [29]. In addition to monotherapy with PARP inhibitors, they have also been

evaluated in combination with other agents or therapies, such as chemotherapy, radiation therapy, and immunotherapy. As shown in previous preclinical studies, PARP inhibitors could enhance

the efficacy of DNA-damaging therapies, such as chemotherapy and radiation therapy, by inhibiting the repair of DNA damage induced by chemotherapy and the growth of tumor cells or by

increasing the number of trapped DNA-PARP complexes (exclusive to temozolomide) [30]. However, a pilot study to assess the safety and efficacy of a combination of veliparib with temozolomide

showed that the combination was well tolerated in patients with prostate cancer but with less benefit [31]. The low dose and low trapping activity of veliparib may limit the efficacy of the

combination. Studies of other combinations of PARP inhibitors and chemotherapy were established as maintenance after several cycles of chemotherapy to avoid major hematologic toxicity and

are still ongoing, as are trials of combination therapy with radiation [32]. In contrast, the combination of AR-targeting drugs and PARP inhibitors showed outstanding synergistic efficacy. A

phase II trial showed that the combination of abiraterone and olaparib prolonged median PFS from 8.2 months to 13.8 months, regardless of mutation status in the HR pathway, in patients with

mCRPC [15]. Further trials, including PROpel, are ongoing to validate the efficacy of the combination of abiraterone and olaparib as first-line therapy. In addition, the combination of PARP

inhibitors with emerging immunotherapy has opened up new avenues to explore. Cohort A of a phase I/II study (NCT02484404) preliminarily enrolled 17 patients with mCRPC who were treated with

durvalumab and olaparib [33]. This study demonstrated the efficacy of this combination therapy, particularly in patients with DDR aberrations. A further study, KEYNOTE-365, enrolled 41

patients with no DDR aberrations to study the efficacy of the combination of olaparib and pembrolizumab [34]. The results of the trial showed a composite RR of ~15%. Based on this, an

ongoing phase III trial (KEYLYNK-010) is comparing the efficacy of pembrolizumab plus olaparib to abiraterone acetate or enzalutamide. In addition, a phase II trial is examining whether

olaparib combined with durvalumab could replace the standard treatment for prostate cancer. Another trial focused on whether cetrelimab or abiraterone is the better choice for combination

therapy with niraparib (NCT03431350). A summary of ongoing phase II and/or III clinical trials on PARP inhibitors is presented in Table 1. As reported in the TOPARP-A trial, 2 of the 16

responders could not be recognized using the biomarkers included in this trial. To expand the population of patients with prostate cancer who will benefit from PARP inhibitors, the current

target is to discover sensitive response prediction biomarkers. Moreover, patients with intrinsic resistance to PARP inhibitors may also benefit from the combination of PARP inhibitors with

synergistic drugs that induce the HRD phenotype. RESPONSE PREDICTION BIOMARKERS In the past decade, several genomic studies have been conducted on prostate cancer. Unlike other common

cancers, prostate cancer was found to have few mutations (0.7 per Mb) [35]. However, mutations occurred more frequently in mCRPC (4.4 per Mb) [36]. Furthermore, it was found that recurrent

mutations of mCRPC belong to the DNA repair pathway, and the frequency of somatic mutations in the DNA repair pathway in mCRPC is much higher than that in primary prostate cancer (23%–27%

vs. 10%–19%) [36, 37]. These characteristics of genomic alterations in mCRPC may enhance the antitumor effect of PARP inhibitors. Alterations in the DNA repair pathway or those affecting the

function of DNA repair, which may be response prediction biomarkers for treatment with PARP inhibitors, are summarized in Table 2. The interactions of PARP inhibitors and genetic

aberrations in DSBs are summarized in Fig. 1b. _BRCA1/2_ MUTATIONS Both BRCA1 and BRCA2 play key roles in different processes in HR. BRCA1 is involved in ssDNA formation at the DSB site and

then joins the RAD51 recombinase onto the forming ssDNA [38]. BRCA2 participates in joining RAD51 onto ssDNA [39]. _BRCA1/2_ mutations cause a deficiency in HR and lead to synthetic

lethality with PARP inhibitors. They are the most explicit response prediction biomarkers, and their detection is necessary not only in patients with mCRPC but also in patients with primary

prostate cancer. For example, a patient with mCRPC who exhibited remarkable radiological and biochemical responses to the PARP inhibitor veliparib was retrospectively detected with somatic

_BRCA2_ biallelic (homozygous) loss in the primary tumor, which was collected 18 months before progression to the CRPC stage [40]. Progression to mCRPC may be delayed if a _BRCA1/2_ mutation

assay is performed on the primary tumor and earlier treatment with a PARP inhibitor is applied. The first _BRCA1/2_ mutation assay, known as the Myriad BRACAnalysis CDx® assay, was approved

for detecting a germline _BRCA1/2_ mutation for the indication of olaparib by the FDA. Another assay, named FOUNDATIONFOCUS™ CDxBRCA, was approved by the FDA as a companion diagnostic test

for rucaparib. This is the first assay based on next-generation sequencing (NGS) and was able to detect both germline and somatic _BRCA1/2_ mutations for the precise administration of a PARP

inhibitor. ATAXIA-TELANGIECTASIA MUTATED (_ATM_) ALTERATIONS ATM is a DNA damage sensor that is recruited to DSB lesions and promotes G1/S cell cycle arrest by the activation of CHK2 and

the stabilization of p53 [41]. It was reported that ATM inactivation increased sensitivity to PARP inhibitors, as mediated by mitotic catastrophe, independent of apoptosis in lymphoid tumor

cells [42]. In Mateo’s study, 4 of 5 patients with CRPC with ATM alterations presented sensitivity to PARP inhibitors [10]. However, recent preclinical and clinical studies found that

ATM-deficient tumors did not truly benefit from PARP inhibitors and were much more sensitive to the combination of ATR inhibitors and PARP inhibitors [28, 43,44,45]. This may be because ATM

functions as a DNA damage sensor that does not directly execute DNA repair. SPECKLE-TYPE POZ (_SPOP_) MUTATIONS The SPOP protein is a component of the cullin-3-based ubiquitin ligase complex

that ubiquitinates target proteins and was demonstrated to be involved in the DDR [46]. Recent genomic analyzes have shown that SPOP is the most frequently mutated gene and that the

frequency of SPOP mutations is 11%–13% in patients with prostate cancer [47, 48]. SPOP mutations are exclusive to ETS family gene rearrangements and are enriched with

rearrangement-associated deletions such as _CHD1_ deletion [47, 48]. Moreover, a study demonstrated that SPOP mutations were associated with increased sensitivity to PARP inhibitors by

impairing HR and facilitating nonhomologous end-joining (NHEJ) [49]. Although the underlying mechanism is unclear, SPOP mutations are potential biomarkers for PARP inhibitor therapy. _CHD1_

DELETION _CHD1_ deletion, accompanied by SPOP mutations, occurs frequently in prostate cancer [36, 37, 47]. CHD1 equilibrates the selection of HR and NHEJ. The loss of CHD1 stabilizes 53BP1,

which induces an increase in error-prone NHEJ. Meanwhile, it impedes the recruitment of HR proteins, which induces impaired error-free HR and genomic instability [50,51,52]. Consequently, a

dramatic increase in genomic instability facilitates the effect of PARP inhibitors in prostate cancer. _CHD1_ deletion may serve as a biomarker for the treatment of PARP inhibitors.

RIBONUCLEASE H2B (_RNASEH2B_) DELETION A recent CRISPR screening study found that mutations in three genes encoding ribonuclease H2 (RNASEH2A, RNASEH2B, and RNASEH2C) were associated with

increased sensitivity to PARP inhibitor therapy [53]. The deletion of ribonuclease H2 leads to impaired ribonucleotide excision repair and induces another ribonucleotide excision pathway

mediated by topoisomerase 1, which eventually causes genomic instability and PARP-trapping DNA lesions [54]. Significantly, the loss of _RNASEH2B_ was found in 35.4% of patients with mCRPC

[53]. The relationship between _RNASEH2B_ deletion and PARP inhibitor sensitivity needs to be further assessed. _TMPRSS2–ERG_ FUSION AND _PTEN_ DELETION Both _TMPRSS2–ERG_ fusion and _PTEN_

deletion are recurrent gene alterations that play important roles in the progression of prostate cancer [55, 56]. _PTEN_ deletion occurs with _ERG_ rearrangement, as the second event

following _ERG_ rearrangement [57], and was demonstrated to be sensitive to PARP inhibitors by reducing RAD51 in some sporadic tumors [58, 59]. However, _PTEN_ deletion did not affect HR

function or RAD51 recruitment and resulted in only mild sensitivity to PARP inhibitors in prostate cancer [60]. _TMPRSS2–ERG_ fusion consists of an upstream _TMPRSS2_ gene promoter and a

downstream _ERG_ coding region. Among these, the _TMPRSS2_ gene promoter is driven by AR, and ERG is an oncogenic transcription factor. The fusion product physically interacts with PARP1 and

DNA-PKcs, and the overexpressed fusion product induces DNA DSB formation, enhancing the effect of PARP inhibitors [27]. Furthermore, it was found that prostate tumors with ETS gene fusion

were sensitive to PARP1 inhibition in a mouse xenograft model [27]. The combination of irradiation and PARP inhibitors appears more effective in patients with _TMPRSS2-ERG_ fusion [61, 62].

A phase I clinical trial found that neither _ETS_ fusion nor _PTEN_ deletion was associated with PARP inhibition in prostate cancer [63]. Consistent with this, a phase II study reported that

_ETS_ fusions could not predict the response to PARP inhibitors [64]. NON-BRCA DDR GENE ALTERATIONS Other non-BRCA DDR gene alterations may cause sensitivity to PARP inhibition by impairing

HR function. For example, alterations in _PALB2_, _RAD51B_, _FANCA_, and _BRIP1_ were also potential predictive biomarkers [13, 28, 65]. However, not all DDR gene alterations, such as gene

alterations in _ATM_, _CDK12_, and _CHEK2_, confer clear benefits from PARP inhibitors [13, 28, 65]. In addition, alterations in genes other than DDR, which may also result in increased DNA

damage, lead to sensitivity to PARP inhibition. KMT2D is an epigenetic modifier, and the loss of _KMT2D_ causes DNA damage through the accumulation of ROS and increases the sensitivity to

PARP inhibitors [66]. The predictive biomarkers for gene alterations are not fully understood. To avoid ignoring alterations in other pathways that may result in HRD, biomarkers in the

genomic footprint (HRD mutational signature, genomic instability) or functional assays (γH2AX-RAD51 nuclear foci formation), which directly detect the capacity of DNA repair, should be

considered. SYNERGISTIC COMBINATION STRATEGIES In addition to determining all beneficiaries of PARP inhibitor therapy by more precise assessment, another way to increase the beneficiaries is

to find synergistic combinations with PARP inhibitors. The combination of PARP inhibitors and immunotherapy or AR-targeting drugs showed great potential from clinical data, and targeted

drugs such as ATR inhibitors are under clinical investigation. Meanwhile, some drugs that impair the HR function, which may induce synthetic lethality in combination with PARP inhibitors,

are still in preclinical testing. Recent studies of potential synergistic combinations in the preclinical and clinical stages are summarized in Table 3. AR INHIBITION A previous study found

that AR amplification occurred in 30% of recurrent tumors, whereas no amplification was found in ADT-naive primary tumors [67]. In addition to the increase in AR expression, CRPC tumors were

also found to be enriched in alterations in the DNA damage repair pathway. Furthermore, crosstalk between AR and DNA damage repair was discovered recently. There are three major aspects of

this process: (1) AR positively regulates the transcription of genes in different DNA repair pathways, such as HR, NHEJ, and MMR [68,69,70]; (2) there is a feedback loop between PARP1 and

AR, which means that PARP1 is transcriptionally regulated by AR and is a cofactor of AR transcriptional activity [11, 69]; and (3) AR increases NHEJ capacity by inducing DNA-PKcs expression,

and in turn, DNA-PKcs is required for AR transcription activity [68]. AR inhibitors induce synthetic lethality with PARP inhibitors by impairing the DNA repair function. Meanwhile, PARP

inhibitors could hinder the transcriptional activity of AR, which facilitates the antitumor effect of AR inhibitors. These interactions between AR and DNA damage repair induce synthetic

lethality between AR inhibitors and PARP inhibitors [71, 72]. In a phase II trial, researchers observed a significant increase in radiographic progression-free survival (rPFS) in patients

with mCRPC for the combination of olaparib and AR inhibitor compared with the AR inhibitor alone [15]. However, the combination of veliparib and an AR inhibitor did not affect the treatment

of abiraterone plus prednisone in PSA RR, measurable disease RR (mRR), or median PFS [64]. It was difficult to determine the cause of the discrepancies between these two trials. Part of the

reason for the discrepancies may be the weaker PARP-trapping activity of veliparib. Given the limitation of the small sample size of the two trials, larger trials are needed to clarify the

benefit of the combination of an AR inhibitor and a PARP inhibitor. In addition, the frequencies of serious adverse events were reported to be ~34% with the combination of olaparib and

abiraterone and 18% with abiraterone alone. The increased serious adverse effects caused by the combination should be considered. IMMUNE CHECKPOINT BLOCKADE When focusing on programmed death

1/programmed death-ligand 1 (PD-1/PD-L1)-targeting antibodies in prostate cancer, researchers found that a PARP inhibitor could increase the expression of PD-L1 in tumors with wild-type or

_BRCA_ mutants and that DNA damage induced by PARP inhibitors could increase neoantigens [73,74,75,76]. This effect of the PARP inhibitor increased the therapeutic targets of immune

checkpoint blockade. Based on the rationale of synergism, the combination of durvalumab and olaparib was demonstrated to be efficacious, particularly in men with DDR abnormalities [33]. In

addition, the treatment of patients with no DDR aberrations with a combination of olaparib and pembrolizumab resulted in a composite RR of ~15% [34]. The combination of a PARP inhibitor and

immune checkpoint blockade increased the population sensitivity to immune checkpoint inhibitors. Moreover, it may be a better choice than immune checkpoint blockade monotherapy for patients

with and without DDR abnormalities. TARGETED AGENTS The combination of PARP inhibitors with some targeted agents is also a potential strategy. In research on ATM alterations, preclinical

data showed that olaparib induced reversible G2 arrest but was not cytotoxic in ATM-deficient cell lines [77, 78]. Clinical data also showed that few patients with ATM alterations were

sensitive to PARP inhibitors [13, 28]. It is necessary to explore other therapies in patients with ATM alterations [79]. Preclinical studies found that the combination of olaparib and an ATR

inhibitor could induce cell death in ATM-deficient cells [77, 78]. This was considered to be mediated by the ablation of G2 arrest induced by ATR inhibitors. Furthermore, the combination

was cytotoxic in BRCA-deficient cells [80]. However, the rationale behind the synergism was not clear. Therefore, ATR inhibitors may be a new combination option with PARP inhibitors for

patients with ATM alterations or even HR-deficient patients [43]. The TRAP clinical trial is studying the combination of olaparib and the ATR inhibitor AZD6738, with the enrolled patients

being grouped into a DNA repair-proficient cohort and a deficient cohort. Similarly, the anti-angiogenic agent cediranib could suppress the expression of BRCA1/2 and RAD51 in addition to

having an anti-angiogenic effect [81]. This unexpected function in DDR proteins may induce synthetic lethality with the combination of PARP inhibitors by impairing HR function. It was

reported that this combination could significantly prolong rPFS in unselected patients with mCRPC [82]. In addition, as described above, PARP inhibitors show modest efficacy in

PTEN-deficient prostate cancer. It was found that olaparib exposure may superactivate the PI3K-Akt signaling pathway [83]. Consequently, the addition of a PI3K inhibitor could greatly

increase the efficacy of PARP inhibitors by blocking Akt activation [83]. The efficacy of this combination has been studied in clinical trials (NCT03586661, NCT03586661). COMBINATION DRUGS

IN PRECLINICAL TESTING NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction in various quinones, including β-lapachone, by using NADH or NAD(P)H as electron donors.

NQO1 is overexpressed in many solid tumors, including non-small cell lung cancer and breast cancer [84]. In NQO1-overexpressing cancer cells, the administration of β-lapachone was found to

produce hydrogen peroxide (H2O2) via NQO1-dependent futile redox cycling. H2O2 induced an increase in DNA base and SSB lesions, which caused PARP1 hyperactivation. The hyperactivation of

PARP1 resulted in dramatic NAD+/ATP depletion and ultimately led to caspase-independent programmed necrosis [85]. This anticancer effect of β-lapachone is dependent on the high expression of

NQO1. Furthermore, it was reported that the addition of PARP inhibitors blocked the function of PARP1 and maintained the level of the NAD(P)H pool, which was required for NQO1-dependent

futile redox cycling, and subsequently induced an increase in H2O2 [86]. The significant increase in H2O2, which could not be repaired due to the inhibition of PARP, ultimately induced

tumor-selective apoptosis [86]. This mechanism of the combination of β-lapachone and a PARP inhibitor led to synthetic lethality in NQO1-overexpressing cancer cells [86]. Immunohistochemical

analysis by Ying Dong et al. found that ~60% of prostate tumors had elevated NQO1 levels compared with paired normal tissue [87]. This suggested that β-lapachone is a potential drug for use

in combination with PARP inhibitors for prostate tumors with a high expression of NQO1. More preclinical and clinical studies need to be performed to examine this synergistic combination.

Polo-like kinase 1 (PlK1) is overexpressed in prostate cancer and associated with tumorigenesis and the progression of prostate cancer [88]. As reported by Li et al., the use of a PARP

inhibitor caused the accumulation of the cell cycle in the G2/M phase and increased the expression of PlK1 in p53-mutant prostate cancer cells [89]. In these circumstances, the addition of a

PlK1 inhibitor dramatically decreased the expression of PARP1 and inhibited tumor growth together with a PARP inhibitor. However, in wild-type p53 cells, the use of a PARP inhibitor did not

upregulate the expression of PlK1, and no synergistic effect was found for the combination of a PARP inhibitor and a PlK1 inhibitor. Owing to p53-mediated cell cycle arrest, the DNA damage

induced by PARP inhibitors could not induce progression into the G2/M phase and resulted in failure to upregulate PlK1. As expected from this observation, the addition of a p53 inhibitor to

the combination of a PARP inhibitor and a PlK1 inhibitor again showed synergism in wild-type p53 cells. It should be noted that the synergism described above was independent of BRCA status.

This finding may broaden the population of patients who could benefit from this treatment, regardless of their _p53_ and _BRCA1_ status, by the combined inhibition of the PlK1, p53, and PARP

proteins. HDAC inhibitors can decrease the expression of proteins involved in HR and increase the sensitivity to PARP inhibitors in many cancers, including prostate cancer [90,91,92].

Recently, the mechanism behind the synergistic effect of an HDAC inhibitor and a PARP inhibitor was reported to be that the inhibition of HDAC decreased the protein stability of BRCA1 by

reducing the protein expression of UHRF1 [93]. In addition, the transcription of _UHRF1_ could be upregulated by the binding of FOXM1 to the promoter of _UHRF1_ [94]; simultaneously, FOXM1

inhibition could inhibit the progression of prostate cancer cells by impairing AR function [95, 96]. FOXM1 overexpression is associated with taxane and paclitaxel resistance by regulating

the transcription of _UHRF1_ and _ABCC5_ in prostate cancer [94, 97]. Moreover, FOXM1 inhibition increased the sensitivity of PARP inhibitors by inducing BRCAness in high-grade serous

ovarian cancer or non-serous epithelial ovarian cancer [98, 99]. Nevertheless, it remains unknown whether FOXM1 inhibition can enhance the sensitivity of prostate cancer to PARP inhibitors.

CONCLUSIONS With the rapid development of sequencing technologies, systematic genomic sequencing analyzes have found that recurrent mutations in mCRPC are focused on the DNA repair pathway

in both germline and somatic specimens. This suggests the potential efficacy of PARP inhibitors in patients with mCRPC. The results of the TOPARP-A study supported a breakthrough therapy

designation granted by the FDA for the treatment of patients with mCRPC and _BRCA1/2_ or ATM mutations. Moreover, patients with germline DNA damage repair gene mutations were more likely to

progress to castration-resistant status. Thus, the early use of PARP inhibitors in patients with prostate cancer or mCRPC and DNA damage repair mutations may slow the progression to

castration resistance [40, 100]. Although biomarkers to predict the response of PARP inhibitors extend from germline _BRCA1/2_ mutations to germline and somatic alterations in the DNA repair

pathway, there are still some responders to PARP inhibitors that cannot be recognized by current biomarkers. Genomic signatures and functional assays are not restricted to the function of a

single gene; they are representative of the effect of HRD on the genome and the DNA repair capacity of tumor cells, respectively. Thus, these may serve as supplementary techniques for use

with current biomarkers to identify sensitive patients. In addition, the development of new techniques has afforded the possibility of monitoring mutations during disease progression. For

example, even if patients were detected to have positive biomarkers at the beginning of treatment, there is still the potential that resistance to PARP inhibitors will be acquired [101].

Conversely, the identification of positive biomarkers, which were not found during the initial treatment but were found by rebiopsy along with disease progression, provides a chance to

choose PARP inhibitors [102]. This evidence indicates the necessity of rebiopsy to detect gene alterations related to acquired resistance and terminate ineffective treatment with a PARP

inhibitor or to find newly emerged positive biomarkers that warrant the addition of a PARP inhibitor to the treatment plan. Given the rapid development of liquid biopsy, cell-free DNA

extracted from plasma has become a priority choice for rebiopsy [103, 104]. However, further research is still required to determine whether the combination of drugs could cause HRD in

HR-proficient tumors and ultimately induce synthetic lethality [105]. A phase II clinical trial (NCT01972217) reported the synergistic efficacy of the combination of olaparib and abiraterone

in unselected patients with mCRPC. A larger number of patients with or without HRD is required to analyze whether this efficacy is independent of HR repair mutation status. Moreover, the

risk of toxicity increases with an increase in effectiveness, and as safety is always the primary concern, the assessment of the risk and effectiveness before administration, dose intensity

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Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the National Key Research and Development Program of China (2016YFC1306900), National Natural Science Foundation of

China (81874327), Key Research and Development Program of Hunan Province (2019SK2251), and Innovation and Research Project of Development and Reform Committee of Hunan Province (2019-875).

AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders,

Xiangya Hospital, Central South University, Changsha, 410008, China Yi-xin Chen, Ma-sha Huang, Ji-ye Yin, Wei Zhang, Hong-hao Zhou & Zhao-qian Liu * Institute of Clinical Pharmacology,

Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, China Yi-xin Chen, Ma-sha Huang, Ji-ye Yin, Wei

Zhang, Hong-hao Zhou & Zhao-qian Liu * Department of Pharmacy, The Second People’s Hospital of Huaihua City, Huaihua, 418000, China Li-ming Tan & Jian-ping Gong Authors * Yi-xin Chen

View author publications You can also search for this author inPubMed Google Scholar * Li-ming Tan View author publications You can also search for this author inPubMed Google Scholar *

Jian-ping Gong View author publications You can also search for this author inPubMed Google Scholar * Ma-sha Huang View author publications You can also search for this author inPubMed 

Google Scholar * Ji-ye Yin View author publications You can also search for this author inPubMed Google Scholar * Wei Zhang View author publications You can also search for this author

inPubMed Google Scholar * Hong-hao Zhou View author publications You can also search for this author inPubMed Google Scholar * Zhao-qian Liu View author publications You can also search for

this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Zhao-qian Liu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Chen, Yx., Tan, Lm., Gong, Jp. _et al._ Response prediction biomarkers and drug combinations of PARP inhibitors in

prostate cancer. _Acta Pharmacol Sin_ 42, 1970–1980 (2021). https://doi.org/10.1038/s41401-020-00604-1 Download citation * Received: 10 July 2020 * Accepted: 20 December 2020 * Published: 15

February 2021 * Issue Date: December 2021 * DOI: https://doi.org/10.1038/s41401-020-00604-1 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:

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prostate cancer * PARP inhibitors * response prediction biomarkers * synergistic combination strategies