The role of PARP inhibitors in the treatment of prostate cancer

Many people don’t understand the use of PARP inhibitors in prostate cancer, and are even less clear about when to use them. Therefore, I’ve written this article to clarify this issue, starting with tumor characteristics and the mechanism of action of PARP inhibitors. I hope this will be helpful to patients and friends!

Section 1: Molecular Basis of PARP Inhibitors in Cancer Therapy

1.1 DNA Damage Response (DDR) Network: Overview of BER and HRR Pathways

To maintain genomic stability and integrity, cells have evolved a sophisticated DNA damage response (DDR) network that includes multiple repair pathways to cope with different types of DNA damage. In the context of prostate cancer, two pathways are particularly critical: base excision repair (BER) and homologous recombination repair (HRR).

The BER pathway is primarily responsible for repairing DNA single-strand breaks (SSBs) and base damage caused by factors such as oxidative stress and alkylating agents. The PARP family of enzymes, particularly the most abundant PARP1, serves as a key “sentinel” in the BER pathway. When a single-strand break (SSB) occurs in DNA, PARP1 rapidly recognizes and binds to the site of damage. Upon binding, PARP1 becomes activated and, using nicotinamide adenine dinucleotide (NAD+) as a substrate, catalyzes the synthesis of long, negatively charged poly(ADP-ribose) (PAR) chains, which are then covalently attached to itself and other target proteins in a process known as PARylation. These PAR chains act as a recruitment platform, attracting and recruiting other key BER repair proteins, such as X-ray repair cross-complementing protein 1 (XRCC1), DNA polymerase, and DNA ligase, enabling efficient repair of single-strand breaks.

Unlike BER, the HRR pathway is responsible for repairing DNA double-strand breaks (DSBs), which are more harmful to cells. If DSBs are not accurately repaired, it can easily lead to chromosomal aberrations, genomic instability, and even cell death. HRR is considered a high-fidelity repair mechanism because it uses intact sister chromatids as templates to accurately repair broken DNA chains. The accuracy of this process depends on a complex network composed of numerous proteins, among which BRCA1 and BRCA2 play an indispensable core role. Because sister chromatids are required as templates, the activity of the HRR pathway is strictly limited to the S phase (DNA replication phase) and G2 phase (late replication phase) of the cell cycle.

1.2 Synthetic Lethality: Exploiting Cancer’s Achilles’ Heel

“Synthetic lethality” is the core theory that explains the highly effective killing effects of PARPi in specific tumors. This genetic concept states that while inactivation of either gene alone does not affect cell survival, simultaneous inactivation of both leads to cell death . The interaction between PARP and the BRCA gene exemplifies the application of synthetic lethality in cancer treatment.

In a cell with normal HRR function, even if the BER pathway is inhibited using PARPi, the cell can still rely on a healthy HRR pathway to repair DSBs that may occur during DNA replication, thereby maintaining survival. Conversely, in a cancer cell carrying a BRCA1/2 gene mutation (which causes HRR function deficiency, or HRD), although its main pathway for repairing DSBs is impaired, the cell can still barely maintain genomic stability through other repair pathways such as BER and survive.

PARPi’s therapeutic strategy takes advantage of this inherent defect of cancer cells. When PARPi is applied to an HRD cancer cell carrying a BRCA1/2 mutation, two key DNA repair pathways in the cell – BER and HRR – are blocked. PARPi inhibits the BER pathway, resulting in the inability to repair SSBs in time and their continuous accumulation. When the cell enters the S phase for DNA replication, the replication fork encounters these unrepaired SSBs, causing the replication fork to stall and collapse, and then produce a large number of highly toxic DSBs. Because the cancer cell itself has HRR defects, it is unable to effectively repair these newly generated DSBs, which ultimately leads to large-scale genomic instability, chromosome breakage, and the initiation of cell apoptosis, thereby achieving selective killing of cancer cells, while having little effect on healthy cells with normal HRR function.

1.3 Dual roles of PARP1: catalytic repression and chromatin capture

The initial model believed that the therapeutic effect of PARPi was mainly due to its inhibition of PARP enzyme catalytic activity, thereby preventing the synthesis of PAR chains and leading to the accumulation of SSBs. However, subsequent in-depth research revealed a more critical mechanism of action – “PARP trapping”.

PARPi not only competitively binds to the NAD+ binding pocket of the PARP1 enzyme, inhibiting its catalytic activity, but more importantly, this binding causes a change in the conformation of the PARP1 protein, “locking” it at the site of DNA damage, forming a stable and highly cytotoxic “PARPi-PARP1-DNA” tripartite complex. This trapped complex itself is a huge physical obstacle that severely hinders key cellular life processes such as DNA replication and transcription. Compared to the mere accumulation of SSBs, this physical barrier is much more lethal to cells.

Different PARPi have different capture efficiencies, which are not entirely proportional to their catalytic inhibition ability (i.e., IC50 value). For example, Talazoparib is considered to be an extremely strong PARP capture agent, while Veliparib has a relatively weak capture ability. This difference in capture efficiency largely explains the different efficacy and toxicity characteristics of different PARPi in preclinical and clinical studies. Therefore, the research and development and evaluation of modern PARPi has shifted from simply pursuing the inhibition of enzyme activity to optimizing the capture ability of the drug in order to form more stable and more lethal protein-DNA complexes in tumor cells.

1.4 Link to cell proliferation: How replication stress drives cytotoxicity

The synthetic lethal effect of PARPi is not a static process. It is closely related to the proliferation state of cells, especially the S phase of the cell cycle, which is a prerequisite for PARPi to exert its maximum killing effect.

The root cause of PARPi-induced cytotoxicity lies in the dramatic increase in replication stress. During the S phase, when the DNA replication fork advances along the template chain, once it encounters the captured PARP1-DNA complex, the replication fork will be blocked, stalled, and eventually collapse. The collapse of the replication fork is a key step in the generation of lethal DSBs, and these DSBs are the type of damage that HRD cells cannot repair. Studies have shown that PARPi treatment leads to a delay in S phase progression and induces the formation of single-stranded DNA gaps (ssGAPs) during replication, especially during the processing of Okazaki fragments on the lagging chain. These ssGAPs are a key form of damage that predicts drug sensitivity.

Therefore, the efficacy of PARPi is based on a clear dual premise: first, a genetic vulnerability of the cell, namely, the presence of a defect in the HRR pathway (answering the “what” question); second, the physiological state of the cell, namely, an active proliferation cycle (answering the “when” question). A cancer cell carrying a BRCA mutation but in a quiescent (G0) or slowly proliferating state may be less sensitive to PARPi due to the lack of active DNA replication to convert drug-induced damage into irreparable DSBs. This understanding has important guiding implications for clinical practice. For example, tumor proliferation indices (such as Ki-67 levels) may become potential biomarkers for predicting PARPi efficacy.

Section 2: Genetic Mapping of Homologous Recombination Deficiency in Prostate Cancer

Accurate selection of patients who can benefit from PARPi treatment is the key to achieving personalized treatment.

2.1 Prevalence and spectrum of HRR gene alterations in prostate cancer

Alterations in HRR pathway genes are not uncommon in prostate cancer, and their incidence increases significantly with disease progression. Data from multiple large-scale genomic sequencing studies indicate that approximately 20% to 30% of tumors in patients with metastatic castration-resistant prostate cancer (mCRPC) harbor pathogenic alterations in HRR genes. This proportion is lower in localized prostate cancer, at approximately 5% to 10%, suggesting that HRR defects may be associated with tumor invasion and metastasis.

These genetic alterations can be divided into two major categories: germline mutations and somatic mutations. Germline mutations are heritable and present in every cell of the patient, while somatic mutations are acquired later in life within tumor tissue. Approximately 12% to 16% of patients with mCRPC carry germline HRR mutations, and the overall mutation rate is even higher if somatic mutations are included. This finding is crucial not only for treatment selection for the patient but also for assessing the risk of hereditary cancer for their family members.

2.2 Key genes conferring sensitivity to PARP inhibitors: beyond BRCA1/2

Although BRCA1 and BRCA2 (particularly BRCA2) are the most common HRR genes in prostate cancer and most closely associated with PARPi efficacy, the sensitivity spectrum is much broader. In patients with mCRPC, the mutation rate of BRCA2 is approximately 5% to 13%, and it is the strongest predictor of high sensitivity to PARPi.

However, clinical trial inclusion criteria and authoritative guidelines such as the NCCN have recognized a broader list of HRR genes, whose mutations may also sensitize tumors to PARPi. These genes include (but are not limited to): ATM, PALB2, CHEK2, CDK12, FANCA, RAD51D, BRIP1, RAD51B, RAD51C, RAD54L, BARD1, etc.

Crucially, not all HRR gene mutations are clinically equivalent; a distinct “sensitivity hierarchy” exists among them. Patients with BRCA1/2 mutations (particularly those with biallelic inactivation) have the highest response rates to PARPi and the most significant clinical benefits. In contrast, patients with mutations in genes such as ATM or CHEK2 may have tumors with lower homologous recombination deficiency (HRD score) and significantly lower responses to PARPi, with no significant survival benefit observed in some analyses. This difference in sensitivity stems from the distinct functions and importance of these proteins in the HRR pathway. For example, BRCA2 is directly involved in the loading of RAD51 protein onto DNA break ends and is central to the execution phase of HRR. ATM, on the other hand, primarily acts as an upstream damage signal sensor and activator, and its functional loss may not affect HRR as radically as BRCA2 loss. This gradation imposes higher requirements on clinical decision-making, requiring that all patients with “HRR mutation-positive” status not be simply treated as a homogenous group.

2.3 Clinical Necessity of Biomarker Testing

These data clearly indicate that comprehensive genomic testing of patients with metastatic prostate cancer has become an essential component of modern clinical practice. Internationally recognized guidelines, such as the NCCN, strongly recommend germline and/or systemic HRR gene testing for patients with metastatic prostate cancer.

Testing can be performed in a variety of ways. Traditional tissue biopsy (including tumor tissue from primary or metastatic lesions) is the gold standard, allowing direct analysis of the genetic status of tumor cells. In recent years, liquid biopsy technology, which involves detecting circulating tumor DNA (ctDNA) in peripheral blood, has provided a less invasive and more reproducible method for dynamically monitoring the evolution of the tumor genome, which is of great value in assessing treatment resistance and discovering new therapeutic targets.

An ongoing challenge in clinical practice is how to interpret variants of unknown significance (VUS). Although these gene sequence changes have been detected, it is unclear whether they actually lead to loss of protein function and affect clinical outcomes, which brings some confusion to clinical decision-making.

Table 1: Prevalence of key HRR gene alterations in metastatic prostate cancer and associated PARP inhibitor sensitivity

Gene	Approximate prevalence of mCRPC (germline + lineage)	Related PARPi sensitivity	Supporting evidence
BRCA2	8% – 13%	high	Highest response rate and most significant survival benefit demonstrated in PROfound trial; high HRD score
BRCA1	1% – 2%	high	The clinical benefit is clear, but the data are relatively limited due to the low mutation rate.
ATM	6% – 12%	Low/Uncertain	PROfound trial subgroup analysis showed no significant survival benefit; HRD score was lower
PALB2	~0.5% – 1%	Moderate	Functionally closely linked to BRCA2, it is considered an important predictor of susceptibility, but data are limited.
CHEK2	2% – 5%	Low/Uncertain	Clinical data showed low response rate; low HRD score
CDK12	4% – 6%	Moderate/uncertain	Associated with genomic instability, but sensitivity to PARPi is still under investigation, and some studies have shown response
Other HRR genes	Each <1%	uncertain	Including RAD51C/D, BRIP1, FANCA, etc., are listed as potential targets, but individual data are scarce and the clinical significance needs further verification

Section 3: Clinical Evidence in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Metastatic CRPC (mCRPC) is a lethal stage of prostate cancer with limited treatment options. The emergence of PARPi has revolutionized treatment in this area. This section systematically reviews and analyzes the key phase III clinical trials that established PARPi as the standard of care in mCRPC, tracing the evolution of its clinical application from late-line monotherapy to first-line combination therapy.

3.1 Monotherapy after prior androgen receptor pathway inhibitor (ARPI) treatment: the landmark PROfound trial

The PROfound trial (NCT02987543) is the first phase III randomized controlled study to demonstrate the success of PARPi in mCRPC patients selected by molecular markers, and its results have changed the treatment landscape of mCRPC.

• Trial Design : This study enrolled patients with mCRPC whose disease progressed after prior treatment with a novel ARPI (such as enzalutamide or abiraterone ). All patients required confirmed HRR gene alterations via tumor tissue genetic testing. Patients were divided into two cohorts based on mutation type: Cohort A included patients with BRCA1, BRCA2, or ATM gene mutations and served as the primary analysis population; Cohort B included patients with mutations in 12 other prespecified HRR genes (such as PALB2 and CDK12). Patients were randomly assigned in a 2:1 ratio to receive either olaparib monotherapy or a control treatment (an alternative ARPI) of their choice.
• Efficacy in Cohort A : The trial successfully met its primary endpoint. In Cohort A, olaparib treatment significantly prolonged radiographic progression-free survival (rPFS) compared to the control group. The median rPFS was 7.4 months in the olaparib group compared to 3.6 months in the control group, representing a 66% reduction in the risk of disease progression or death (hazard ratio = 0.34).
• Overall survival (OS) benefit : Although up to 67% of patients in the control group crossed over to the olaparib group after disease progression, which may have diluted the OS difference, the study still showed a statistically significant overall survival benefit. The median OS in the olaparib group was 19.1 months, significantly better than 14.7 months in the control group (HR = 0.69).
• Gene-specific analysis : In-depth exploration of the PROfound trial data further confirmed the aforementioned concept of “sensitivity hierarchy”. The overall benefit of the trial was mainly driven by the patient population carrying BRCA1/2 mutations. In this subgroup, Olaparib’s efficacy was more prominent, with a median rPFS of 9.8 months (HR = 0.22). In sharp contrast, exploratory analysis showed that the subgroup of patients carrying only ATM mutations did not gain a significant survival benefit from Olaparib treatment. This finding has important clinical guidance significance, indicating that the specific gene type must be considered when interpreting “HRR mutation positivity”.

Based on the positive results of the PROfound trial, the U.S. Food and Drug Administration (FDA) and multiple global regulatory agencies approved Olaparib for the treatment of patients with HRRm mCRPC who had progressed after previous treatment with enzalutamide or abiraterone, officially establishing PARPi’s therapeutic status in this field.

3.2 Paradigm shift toward first-line combination therapy

After the success of monotherapy, researchers began to explore pushing PARPi to the forefront of treatment and using it in combination with ARPI. The theoretical basis of this strategy lies in the potential synergy between the two. Preclinical studies have shown that the androgen receptor (AR) signaling pathway itself is involved in the transcriptional regulation of DNA repair genes. Therefore, the use of ARPI to potently inhibit AR signaling may downregulate the expression of certain DNA repair proteins, thereby inducing a functional HRD state, the so-called “BRCAness”, in tumors with normal HRR function, thereby enhancing the sensitivity of these tumors to PARPi. This mechanism provides a theoretical basis for the application of PARPi combined with ARPI in the “all-comer” population without biomarker screening, similar to the use of radiation to inhibit HR repair and induce sensitivity to PARPi.

3.2.1 Lynparza combined with Abiraterone (PROpel):

• Trial Design : The PROpel trial (NCT03732820) is a large phase III study evaluating the combination of olaparib and abiraterone as first-line treatment for mCRPC. Patients with mCRPC who were not screened for HRR mutation status were randomly assigned to receive either olaparib plus abiraterone or placebo plus abiraterone.
• Efficacy : The trial met its primary endpoint. In the overall population, the combination therapy group demonstrated significantly improved rPFS compared to the control group, with a median rPFS of 24.8 months versus 16.6 months, respectively, and a 34% reduction in the risk of disease progression (HR = 0.66). Subgroup analysis showed that benefit from the combination therapy was observed in patients with and without HRR mutations, but the benefit was greater in the HRR mutation-positive subgroup (HR for OS, 0.66 versus 0.89, respectively).
• Overall survival : The final OS analysis showed that the median OS in the combination treatment group was extended by 7.4 months (42.1 months vs 34.7 months), but this difference did not reach the pre-specified statistical significance limit (p=0.054).
• Regulatory Interpretation : Although OS did not reach statistical significance, this combination regimen has been approved in some regions (such as the EU) for the first-line treatment of mCRPC, regardless of HRR mutation status (but in cases where chemotherapy is not clinically indicated), based on its strong rPFS benefit and positive OS trend. This reflects the regulatory authorities’ comprehensive consideration of clinical benefits.

3.2.2 Tarazopanib combined with enzalutamide (TALAPRO-2):

• Trial Design : The TALAPRO-2 trial (NCT03395197) is similar in design to PROpel and also evaluates the efficacy of a PARPi (talazoparib) combined with an ARPI (enzalutamide) in the first-line population of patients with mCRPC.
• Efficacy : This trial also yielded positive results. In the overall population, the combination therapy significantly reduced the risk of disease progression or death (HR = 0.63). In the pre-specified HRR-deficient cohort, the efficacy was even more striking, with the median rPFS in the combination therapy group not yet reached, compared to only 12.3 months in the control group (HR = 0.47), demonstrating a substantial clinical benefit.
• Overall Survival : Unlike PROpel, the final OS analysis of TALAPRO-2 showed that in the overall population, the median OS of the combination therapy group reached 45.8 months, significantly better than the 37.0 months in the control group (HR = 0.80). In the HRR-deficient subgroup, the OS benefit was even more significant, with a median OS of 45.1 months and 31.1 months, respectively (HR = 0.62).
• Regulatory interpretation : Although TALAPRO-2 achieved a statistically significant OS benefit in the entire population, the FDA ultimately approved the combination regimen only for mCRPC patients with HRR gene mutations. This seemingly contradictory decision profoundly reflects the regulatory agency’s prudent assessment of the benefit-risk ratio. In the subgroup of patients with normal HRR function, the OS benefit of combination therapy was relatively limited (HR = 0.88), but patients had to endure significantly increased toxicity, especially hematological toxicity (such as the incidence of grade ≥3 anemia as high as 45%). The FDA concluded that for this subgroup, the increased toxicity risk outweighed the limited survival benefit. This decision highlights that when evaluating new therapies, it is important not only to look at the statistical P value, but also to pay attention to the absolute magnitude of clinical benefits and the corresponding safety costs in different patient subgroups.

3.3 Evidence Integration: Positioning of Monotherapy and Combination Therapy in mCRPC

Based on the key trials described above, the treatment strategy for PARPi in mCRPC has become clear. For patients who have failed ARPI treatment and carry sensitive HRR mutations (especially BRCA1/2), PARPi monotherapy (such as olaparib) is the clear standard of care. For first-line mCRPC patients, if HRR mutations are detected, PARPi combined with ARPI (such as talazoparib + enzalutamide) is the preferred option, which provides a significant survival benefit. For patients with unknown HRR function, combination therapy (such as olaparib + abiraterone) is also a viable option, but the differences in benefits and potential toxicity risks in different genetic backgrounds need to be fully communicated with patients.

Table 2: Comparative summary of pivotal phase III trials of PARP inhibitors in mCRPC

Trial (drug)	Number of treatment lines	Patient population	Primary endpoint (median, HR)	Key secondary endpoints (median, HR)	FDA regulatory results
PROfound (Olaparib)	After ARPI treatment	HRRm selection (cohort A: BRCA/ATM)	rPFS: 7.4 vs 3.6 months; HR 0.34	OS: 19.1 vs 14.7 months; HR 0.69	Approved for HRRm
PROpel (olaparib + abiraterone)	First-line	All people	rPFS: 24.8 vs 16.6 months; HR 0.66	OS: 42.1 vs 34.7 months; HR 0.81 (p=0.054)	Approved for BRCAm
TALAPRO-2 (talazopanib + enzalutamide)	First-line	All people	rPFS: not reached vs 21.9 months; HR 0.63	OS: 45.8 vs 37.0 months; HR 0.80 (p=0.016)	Approved for HRRm

Session 4: Expanding into the frontier of hormone-sensitive prostate cancer (HSPC)

With the tremendous success of PARPi in advanced mCRPC, a natural logical extension is: can applying these highly effective drugs earlier in the disease process, that is, in the metastatic hormone-sensitive prostate cancer (mHSPC, also known as mCSPC) stage, bring greater clinical benefit? This section will explore the theoretical basis, preliminary clinical evidence, and future development directions for the use of PARPi in the HSPC stage.

4.1 Theoretical Basis for Early Intervention of High-Risk Diseases

Delivering highly effective therapies to the early stages of the disease is a proven, proven strategy in oncology. The core rationale is that robust intervention at a stage when tumor burden is relatively small, heterogeneity is low, and extensive drug resistance has not yet developed is expected to achieve deeper and more durable remissions, significantly delaying progression to the incurable castration-resistant stage and potentially improving overall survival.

For prostate cancer, mHSPC patients carrying HRR gene mutations are clearly defined as a high-risk population. Compared with patients with normal HRR function, they usually show more aggressiveness, shorter response time to standard endocrine therapy, faster progression to mCRPC, and worse overall prognosis. Therefore, this specific patient group urgently needs a more potent first-line treatment option than the current standard treatment (androgen deprivation therapy combined with ARPI). The synergistic effect and great success of PARPi combined with ARPI in mCRPC provide a solid scientific and clinical basis for testing this strategy in the mHSPC stage.

4.2 Preliminary evidence from the AMPLITUDE trial

The AMPLITUDE trial (NCT04497844) is the first phase III PARPi study to report results in the mCSPC setting, providing preliminary but strong evidence for this novel strategy.

• Trial Design : This study specifically enrolled patients with mCSPC harboring HRR gene mutations and randomly assigned them to receive either niraparib plus abiraterone and prednisone (AAP) or placebo plus AAP.
• Efficacy : The trial successfully met its primary endpoint of rPFS. Results showed that the addition of niraparib significantly improved patients’ rPFS compared to standard of care AAP. In the niraparib combination arm, median rPFS had not yet been reached, compared to 29.5 months in the placebo arm, representing a 37% reduction in the risk of disease progression or death (HR = 0.63). This benefit was even more pronounced in the pre-specified BRCA1/2 mutation subgroup, with a 48% risk reduction (HR = 0.52).
• Other endpoints and safety : The study observed a trend toward improved OS, but due to the short follow-up time, the data are not yet mature. In terms of safety, the combination therapy group had a higher incidence of grade ≥ 3 serious adverse events, mainly including anemia and hypertension, which is consistent with the known toxicity profile of PARPi and AAP.

The results of the AMPLITUDE trial are an important signal in the history of prostate cancer treatment. It confirms for the first time the effectiveness of PARPi targeted therapy for a specific biomarker population in the hormone-sensitive stage. This indicates that the treatment paradigm of prostate cancer is shifting from “sequential treatment” to “early, biomarker-based intensive combination therapy.”

4.3 The Next Wave: Ongoing Trials and Future Outlook in the HSPC Field

The success of the AMPLITUDE trial has opened a new chapter in the treatment of mHSPC, but the exploration of this field has just begun. Currently, multiple large-scale Phase III clinical trials are underway to verify and expand on this discovery.

• EvoPAR-Prostate01 (NCT06120491): This study is evaluating the efficacy of saruparib , a new generation, more selective PARP1 inhibitor, in combination with an ARPI. Saruparib is designed to reduce hematologic toxicity by reducing PARP2 inhibition, potentially improving the therapeutic window. Notably, this study includes both HRR mutation and non-mutation cohorts to explore the potential application of selective PARPi in a wider population.
• TALAPRO-3 (NCT04821622): This study is also evaluating the efficacy of talazoparib plus enzalutamide in patients with mHSPC.

The results of these ongoing studies are highly anticipated. If they confirm and replicate the positive results of AMPLITUDE, the PARPi + ARPI combination regimen could become the new first-line standard of care for newly diagnosed, high-risk mHSPC patients harboring HRR mutations. This would make comprehensive genomic testing at the onset of mHSPC diagnosis no longer just a “recommended” option but a “must-have” step in determining first-line treatment options.

Section 5: Addressing Clinical Challenges: Managing Drug Resistance and Toxicity

Although PARPi has brought significant progress to the treatment of prostate cancer, in clinical practice, physicians and patients still face two core challenges: the emergence of acquired resistance and the management of treatment-related toxicities. This section will explore these challenges in depth and outline the corresponding strategies to address them.

5.1 Emergence of acquired drug resistance: key molecular mechanisms

Like all targeted drugs, despite significant initial efficacy, most tumors will eventually develop resistance to PARPi, leading to disease recurrence. Understanding the resistance mechanism is key to developing subsequent treatment strategies and overcoming resistance. Currently known PARPi resistance mechanisms mainly include:

• Restoration of HRR function : This is the most common and major mechanism of drug resistance. Tumor cells can “bypass” the original HRR defect in a variety of ways.
• BRCA1/2 secondary mutations : New “reverting” mutations occur within the original pathogenic BRCA1/2 mutant gene. These new mutations can restore the protein’s open reading frame, thereby producing a BRCA protein with partial or full function.
• Activation of the alternative pathway : By downregulating the expression of certain proteins (such as 53BP1), the inhibition of DNA end resection is relieved. In cells with BRCA1 mutations, the loss of 53BP1 can partially restore DNA end resection, thereby allowing the HRR pathway to proceed inefficiently and resulting in drug resistance.
• Alterations in PARP1 targets :
• PARP1 expression is downregulated or absent : If tumor cells stop expressing PARP1 protein, PARPi loses its target for binding and “capturing” and becomes ineffective.
• PARP1 gene mutation : The PARP1 gene itself mutates, causing its structure to change, reducing its affinity with PARPi and making it impossible for the drug to bind effectively.
• Replication fork protection : The core killing mechanism of PARPi is to induce replication fork collapse. Therefore, any mechanism that stabilizes stalled replication forks and prevents their collapse could potentially lead to drug resistance. For example, loss of function of certain nucleases (such as MRE11) or proteins that recruit these enzymes (such as PTIP) can protect nascent DNA chains from degradation, thereby allowing cells to survive replication stress.
• Drug efflux : Tumor cells can actively pump out PARPi that has entered the cell by upregulating the expression of drug efflux pumps on the cell membrane (such as P-glycoprotein, P-gp), resulting in insufficient intracellular drug concentration to reach an effective level.

5.2 Safety and Tolerability Characteristics of PARP Inhibitors

Effective management of treatment-related adverse events (AEs) is a prerequisite for ensuring that patients can continue to receive treatment and benefit from it. PARPi, such as olaparib and talazoparib, have similar but not completely overlapping toxicity profiles.

• Common adverse events (all grades) : The most commonly reported side effects included nausea, fatigue/asthenia, anemia, and diarrhea. These symptoms were generally mild to moderate and managed with supportive care.
• Clinically significant adverse events of grade ≥3 : Hematologic toxicity is the most common and often dose-limiting toxicity of PARPi.
• Anemia : The most prominent Grade ≥3 AE among all PARPis. In the PROfound trial, olaparib monotherapy led to dose interruption due to anemia in 25% of patients. The incidence of anemia is even higher in combination therapy regimens. For example, in the TALAPRO-2 trial, the incidence of Grade ≥3 anemia in the talazoparib plus enzalutamide group was as high as 45%.
• Neutropenia and thrombocytopenia : also common and require close monitoring.
• Serious and rare adverse events : Clinicians must be alert to some serious toxicities that occur infrequently but may be life-threatening.
• Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) : This is a treatment-related secondary tumor with an incidence of less than 1.5%, but the consequences are serious and can be fatal.
• Pneumonia : The incidence is less than 1%, but some cases may be fatal, so be alert to new or worsening respiratory symptoms.
• Venous thromboembolism (VTE) , including pulmonary embolism, is at increased risk when PARPi is used in combination with an ARPI. Data from the PROpel trial showed an 8% VTE rate in the olaparib combination group compared to 2.5% in the control group.

5.3 Adverse event management strategies in clinical practice

Proactive management of PARPi toxicity is crucial.

• Baseline assessment and routine monitoring : Before starting treatment, the patient’s baseline complete blood count should be assessed and monitored at least monthly during treatment. For patients with persistent cytopenias, the monitoring frequency should be increased.
• Dose adjustments : Depending on the severity of the adverse event, timely dose suspension and dose reduction are the primary means of managing toxicity. For the most common anemia, multiple dose adjustments may be required, and in severe cases, red blood cell transfusion support may be necessary.
• Patient education : Patients should be informed of possible side effects, especially symptoms of VTE and pneumonia, so that they can seek medical attention promptly.

A thorough understanding and effective management of toxicity are key to determining whether PARPi can be safely used in a wider population. As revealed by the FDA’s review of the TALAPRO-2 trial, significant toxicity (especially hematologic toxicity) in a subgroup of patients with limited benefit may lead to an imbalance in the benefit-risk ratio, thereby limiting the drug’s indications. This highlights the importance of developing a new generation of PARPi (such as PARP1 selective inhibitors) with a better safety profile.

Table 3: Common and serious adverse events of olaparib and talazoparib in mCRPC

Adverse events	Olaparib (single agent – PROfound) % (≥Grade 3)	Lynparza + Abiraterone (PROpel) % (≥Grade 3)	Talazoparib + Enzalutamide (TALAPRO-2) % (≥Grade 3)	Key points of clinical management
hematology
anemia	twenty two%	16%	45%	Most common dose-limiting toxicity; monthly CBC monitoring and dose adjustments or transfusions are required if necessary
Neutropenia	4%	4%	18%	Monitor CBC and be alert to infection risks
Thrombocytopenia	3%	1%	8%	Monitor CBC and be alert to bleeding risk
Gastrointestinal tract
nausea	2%	2%	2%	Usually grade 1-2, treatable symptomatically
Systemic
Fatigue/weakness	3%	4%	4%	Evaluate and exclude other causes and provide symptomatic support
Severe/rare
MDS/AML	<1.5%	<1.5%	<1.5%	Long-term monitoring is required, and medication should be stopped once the diagnosis is confirmed
pneumonia	<1%	<1%	<1%	Be alert to respiratory symptoms and stop taking the drug if diagnosed
VTE	7% (all levels)	8% (all levels)	3% (all levels)	The risk is increased when combined with ARPIs, and patients need risk education and monitoring.

Section 6: Conclusion and Future Outlook

The advent and development of PARP inhibitors has profoundly reshaped the treatment landscape for prostate cancer, pushing molecular biology-based precision medicine to new heights. From initial breakthroughs in advanced patients with specific gene mutations to the significant potential they now demonstrate in first-line treatment and earlier stages of the disease, the clinical application of PARPi continues to expand.

6.1 Integrating PARP inhibitors into modern prostate cancer treatment pathways

Based on the existing high-level evidence-based medicine, the status of PARPi in the treatment pathway of prostate cancer can be summarized as follows:

• For mCRPC :
• For patients who have progressed after previous treatment with new ARPIs and carry sensitive HRR gene mutations (especially BRCA1/2), PARPi monotherapy (such as Olaparib and Rucaparib) is a clear second-line or later-line standard treatment.
• In first-line mCRPC patients, PARPi combined with ARPI (such as talazoparib + enzalutamide) has become the new standard of care for patients with HRR gene mutations. Olaparib combined with abiraterone is also a strong option for patients with BRCA mutations.
• For mHSPC :
• For newly diagnosed high-risk mHSPC patients carrying HRR gene mutations, PARPi combined with ARPI (such as niraparib + abiraterone) is becoming an emerging standard treatment option, which is expected to significantly delay disease progression.

At the core of all these treatment decisions is comprehensive and timely genomic testing . Whether initially diagnosed with mHSPC or at the time of progression to mCRPC, HRR gene testing on tumor tissue or ctDNA is crucial for identifying patients who will benefit most from PARPi therapy.

6.2 Unsolved Mysteries and Future Research Directions

Despite the remarkable achievements, there are still many issues to be explored in the application of PARPi in prostate cancer. Future research directions will focus on the following aspects:

• Optimizing biomarkers : Currently, patient screening relies primarily on lists of gene mutations, but this approach’s predictive power is imperfect. Future research needs to go beyond single gene lists and explore more precise biomarkers. For example, using whole-genome sequencing to analyze tumor “genomic scars” (such as HRD scores) may be able to more accurately reflect the true state of HRR function in tumor cells, thereby identifying patients who do not have classic HRR gene mutations but can still benefit from PARPi.
• Overcoming drug resistance : Developing rational combination therapy strategies to prevent or reverse drug resistance is a key focus in the future. Based on our understanding of the mechanisms of drug resistance, exploring the combined use of PARPi with other targeted drugs such as immune checkpoint inhibitors, ATR inhibitors, and cell cycle inhibitors is expected to bring new hope to drug-resistant patients.
• Expanding to earlier disease stages : With the success in mHSPC, it is inevitable that the role of PARPi will be explored in the neoadjuvant or adjuvant treatment of high-risk localized prostate cancer in the future, in order to eradicate micrometastases and improve cure rates.
• Developing a new generation of drugs : The toxicity of current PARPi, especially hematological toxicity, is the main factor limiting its application. Developing a new generation of PARPi with higher selectivity (e.g., inhibiting only PARP1) and better safety profiles, such as saruparib, is expected to broaden the therapeutic window, allowing more patients to benefit safely and long-term. This is crucial for applying PARPi to a wider population and earlier stages of the disease.

In summary, PARP inhibitors have evolved from a niche drug targeting specific gene mutations to a core component of the prostate cancer treatment arsenal. As our understanding of tumor biology, resistance mechanisms, and drug synergy continues to deepen, the story of PARPi in prostate cancer treatment has just begun.