HRS-1167 (M9466): A Comprehensive Profile of a Next-Generation Selective PARP1 Inhibitor Poised to Redefine a Class

Executive Summary

HRS-1167, also identified as M9466, is an investigational, orally bioavailable, next-generation small molecule inhibitor of Poly (ADP-Ribose) Polymerase 1 (PARP1).[1] Originally developed by Jiangsu Hengrui Pharmaceuticals, the asset is now under global co-development with Merck KGaA following a landmark licensing agreement, underscoring its significant perceived potential in the oncology landscape.[3] The fundamental value proposition of HRS-1167 is rooted in a highly rational drug design strategy: to retain and potentially enhance the profound antitumor efficacy characteristic of the PARP inhibitor class while concurrently mitigating the dose-limiting hematological toxicities that have constrained the therapeutic window and combination potential of first-generation dual PARP1/2 inhibitors.[5]

This strategic objective is substantiated by a compelling preclinical evidence package, most notably the demonstration of a 672-fold selectivity for PARP1 over PARP2, the enzyme isoform strongly implicated in myelosuppression.[5] This high degree of selectivity is hypothesized to uncouple the desired on-target antitumor effects from the off-target toxicities. Early clinical data from the first-in-human Phase 1 monotherapy study (NCT05473624) have provided powerful validation for this approach. In a heavily pretreated patient population with advanced solid tumors harboring Homologous Recombination Repair (HRR) mutations, HRS-1167 demonstrated a remarkable preliminary objective response rate (ORR) of 41.7%.[6] This efficacy signal is particularly noteworthy given that the study population included patients who had previously progressed on other PARP inhibitors. Furthermore, the drug was well-tolerated, with a manageable safety profile and no maximum tolerated dose reached, lending clinical support to the preclinical safety hypothesis.[6]

The external validation of HRS-1167's potential was cemented by the strategic alliance with Merck KGaA, a deal with a potential total value of up to €1.4 billion.[4] This partnership not only provides significant financial backing but also leverages Merck KGaA's global development and commercialization expertise, positioning HRS-1167 for an accelerated and broad development path. The ongoing and planned clinical program is extensive, exploring HRS-1167 as both a monotherapy and in rational combinations with standard-of-care agents across key HRR-deficient tumor types, including ovarian, breast, and prostate cancers.[1] Collectively, the data position HRS-1167 as a potential best-in-class agent with the capacity to overcome the principal limitations of its predecessors, potentially redefining the role of PARP inhibition in modern oncology and expanding its benefits to a wider patient population.

The Evolution of PARP Inhibition: Rationale for a PARP1-Selective Approach

To fully appreciate the strategic and clinical significance of HRS-1167, it is essential to understand the landscape shaped by its predecessors. The development of PARP inhibitors represents one of the most successful applications of targeted therapy in oncology, yet the first wave of these agents brought with it a distinct set of challenges that created a clear and compelling need for a next-generation solution.

Clinical Success and Therapeutic Impact of First-Generation PARP Inhibitors

The first generation of PARP inhibitors—a class that includes the approved agents olaparib, niraparib, rucaparib, and talazoparib—has fundamentally altered the treatment paradigm for a range of malignancies characterized by defects in the HRR pathway.[5] These drugs function through the principle of synthetic lethality. PARP enzymes, particularly PARP1, are critical for repairing single-strand DNA breaks (SSBs) through the Base Excision Repair (BER) pathway.[14] When a PARP inhibitor blocks this function, unrepaired SSBs accumulate and are converted into more complex and cytotoxic double-strand DNA breaks (DSBs) during DNA replication.[12] In healthy cells, these DSBs are efficiently repaired by the high-fidelity HRR pathway. However, in cancer cells that harbor mutations in key HRR genes, such as

BRCA1 and BRCA2, this repair mechanism is defunct. The accumulation of unrepaired DSBs leads to profound genomic instability and, ultimately, apoptotic cell death.[12]

This exquisite sensitivity of HRR-deficient (HRD) tumors to PARP inhibition has led to regulatory approvals and established these agents as a standard of care in several settings, including as maintenance therapy for platinum-sensitive recurrent ovarian cancer, first-line maintenance therapy for advanced ovarian cancer, and for the treatment of BRCA-mutated metastatic breast, pancreatic, and prostate cancers.[13] The clinical benefit has been substantial, significantly improving progression-free survival and, in some cases, overall survival for patients with these difficult-to-treat diseases.[13]

The "Class-Defining" Limitation: Hematological Toxicity

Despite their transformative impact, the clinical utility of first-generation PARP inhibitors is constrained by a significant, class-wide liability: hematological toxicity.[6] Myelosuppression, manifesting as anemia, neutropenia, and particularly thrombocytopenia, is a common and often dose-limiting adverse event associated with these agents.[17] These toxicities frequently necessitate dose interruptions, reductions, or even treatment discontinuation, which can compromise the potential for maximal therapeutic benefit.

The underlying cause of this myelosuppression is believed to stem from the non-selective nature of these first-generation drugs. All currently approved PARP inhibitors are dual inhibitors, targeting both PARP1 and PARP2, and often other PARP family members to varying degrees.[5] A growing body of preclinical and clinical evidence strongly suggests that while PARP1 inhibition is the principal driver of the desired antitumor effect, the off-target inhibition of PARP2 is largely responsible for the observed hematological toxicities.[5] PARP2 has been shown to play a role in hematopoiesis and erythropoiesis, and its inhibition can disrupt the normal development and function of blood cell precursors in the bone marrow.[18] This overlapping toxicity profile poses a major clinical challenge, as it severely limits the ability to combine first-generation PARP inhibitors at full doses with many standard cytotoxic chemotherapies (such as platinum agents or topoisomerase inhibitors) that are themselves myelosuppressive.[19] This limitation has been a significant barrier to exploring the full potential of PARP inhibition in combination regimens and moving these agents into earlier lines of therapy where chemotherapy backbones are common.

The Scientific Imperative for Selectivity

The distinct roles of PARP1 and PARP2 in efficacy and toxicity, respectively, created a clear scientific imperative for the development of a new generation of PARP inhibitors with high selectivity for PARP1. The central hypothesis is that a molecule capable of potently inhibiting and trapping PARP1 while sparing PARP2 could effectively uncouple antitumor activity from dose-limiting hematological toxicity.[14] Such an agent would be expected to possess a significantly improved therapeutic index, leading to better tolerability for patients and allowing for more sustained dosing at optimal therapeutic concentrations.

Perhaps most importantly, a favorable safety profile, particularly with respect to myelosuppression, would unlock the vast potential of combining PARP inhibition with a wide range of other anticancer agents, including conventional chemotherapies and other novel targeted therapies in the DDR space.[19] This rationale forms the very foundation of the HRS-1167 development program. Its design and clinical evaluation are not merely an attempt to create an incremental "me-too" drug, but rather a direct and strategic effort to solve the most significant clinical problem of the entire PARP inhibitor class, potentially redefining its future application in oncology.

HRS-1167: Molecular Profile and Mechanism of Action

HRS-1167 is the embodiment of the rational drug design strategy aimed at optimizing the therapeutic index of PARP inhibition. Its molecular characteristics and mechanism of action are precisely tailored to exploit the vulnerabilities of HRD cancer cells while minimizing collateral effects.

Drug Identity and Characteristics

HRS-1167 is an orally bioavailable small molecule drug currently under investigation for the treatment of various solid tumors.[1] It is referred to interchangeably by several identifiers, including HRS 1167, HRS1167, and M9466, the latter being used predominantly by its co-development partner, Merck KGaA (EMD Serono).[1] While the precise chemical structure is proprietary, patent filings suggest it is a structural analog of AstraZeneca's next-generation PARP1 inhibitor, AZD5305. The structure disclosed in patent application WO2022247816A1, believed to be that of HRS-1167, differs from AZD5305 by the incorporation of a six-membered oxygen-containing ring, a modification intended to optimize its pharmacological properties.[22]

Target Engagement and Dual Mechanism of Action

The primary and highly specific molecular target of HRS-1167 is PARP1.[1] The drug exerts its potent antineoplastic effects through a dual mechanism of action that is characteristic of the most effective PARP inhibitors.

First, HRS-1167 acts as a catalytic inhibitor. It competitively binds to the nicotinamide adenine dinucleotide (NAD+) binding pocket within the catalytic domain of the PARP1 enzyme.[12] This prevents PARP1 from performing its key enzymatic function: the synthesis and transfer of long chains of poly (ADP-ribose) onto itself and other nuclear proteins, a process known as PARylation. PARylation is a critical signaling event that occurs immediately after PARP1 detects a single-strand DNA break. The PAR chains act as a scaffold to recruit other essential DNA repair proteins to the site of damage, initiating the BER pathway. By blocking this catalytic activity, HRS-1167 effectively halts the first step in this crucial DNA repair process.[2]

Second, and perhaps more critically for its cytotoxicity, HRS-1167 is a potent PARP-DNA trapping agent.[5] Beyond simply inhibiting the enzyme's function, the drug physically locks the PARP1 protein onto the DNA at the site of the break. This creates a highly toxic PARP-DNA complex that acts as a physical lesion, obstructing the progression of DNA replication forks.[12] When the replication machinery collides with this trapped complex, the fork can collapse, leading to the formation of a lethal double-strand DNA break.[5] The potency of PARP-DNA trapping is considered a key determinant of a PARP inhibitor's overall antitumor efficacy, and HRS-1167 has been specifically designed to exhibit this activity.[5]

The Principle of Synthetic Lethality

The therapeutic power of HRS-1167 is realized through its exploitation of synthetic lethality in the context of HRD tumors. The double-strand breaks generated by PARP-DNA trapping are not inherently lethal to all cells. In normal, healthy cells with a proficient HRR pathway, these breaks are recognized and accurately repaired, allowing the cell to survive with its genomic integrity intact. However, many cancers, particularly those arising in individuals with germline mutations in genes like BRCA1, BRCA2, PALB2, and others, are deficient in this HRR pathway.[6]

In these HRD cancer cells, the DSBs induced by HRS-1167 cannot be repaired effectively. The cell must then rely on more error-prone, lower-fidelity repair pathways, which are insufficient to handle the high volume of damage. This leads to the accumulation of catastrophic levels of DNA damage, widespread genomic instability, and ultimately triggers programmed cell death (apoptosis).[5] This selective killing of cancer cells that have a specific DNA repair defect, while largely sparing normal cells that do not, is the core principle of synthetic lethality and the foundation upon which the entire therapeutic strategy of HRS-1167 is built.[14]

Preclinical Evidence Package

The decision to advance HRS-1167 into clinical development was underpinned by a robust and highly compelling package of preclinical data. These studies were not only designed to establish proof-of-concept but, more strategically, to build a clear and evidence-based case for its differentiation from and superiority over first-generation PARP inhibitors.

Potency and Unprecedented Target Selectivity

The defining characteristic of HRS-1167 highlighted in its preclinical profile is its combination of high potency and exceptional target selectivity. The molecule is described as a "highly potent" inhibitor of PARP1.[5] The most critical data point supporting its development rationale is its remarkable selectivity. In cellular PARylation inhibition assays conducted in A549 lung cancer cells, HRS-1167 demonstrated a

672-fold greater selectivity for inhibiting PARP1 compared to PARP2.[5] This level of selectivity is a significant leap forward from first-generation agents and forms the cornerstone of the hypothesis that HRS-1167 can deliver potent antitumor efficacy while minimizing the PARP2-mediated hematological toxicities that limit its predecessors. This specific, quantitative demonstration of selectivity was a crucial piece of evidence that de-risked the program and signaled its potential for a superior safety profile in human trials.

Monotherapy Antitumor Activity

Preclinical studies rigorously validated the single-agent efficacy of HRS-1167, confirming its potent synthetic lethal activity in relevant cancer models.

• In Vitro Efficacy: The selective nature of HRS-1167's activity was clearly demonstrated in isogenic cell line models. The drug exhibited potent antiproliferative effects in the DLD-1 colon cancer cell line with a knockout of the BRCA2 gene, but showed no significant activity in the corresponding wild-type DLD-1 cell line, which has a functional HRR pathway.[5] This result provided direct evidence of its specific synthetic lethal mechanism. This finding was expanded upon in a large-scale screen across a panel of 96 different cancer cell lines, where HRS-1167 consistently showed selective antiproliferative activity in various models with BRCA1/2 mutations or other markers of PARP inhibitor sensitivity.[5]
• In Vivo Efficacy: The promising in vitro results were successfully translated into a living model system. In a mouse xenograft model using a BRCA1-mutant human breast cancer tumor, orally administered, once-daily HRS-1167 led to a strong reduction in tumor growth.[5] This study not only confirmed the drug's potent antitumor activity in vivo but also validated its oral bioavailability and favorable pharmacokinetic properties for daily dosing.

Combination Potential and Synergy

A key part of the strategic vision for HRS-1167 is to unlock the full potential of PARP inhibition in combination therapies. The preclinical program was therefore designed to explicitly test this hypothesis. A large in vitro drug combination screen was conducted, testing HRS-1167 with 101 different compounds across 35 cancer cell lines to identify synergistic partners.[5] This screen yielded several promising results, highlighting synergistic or additive activity when HRS-1167 was combined with:

• Other DNA Damage Response (DDR) Inhibitors: Strong synergy was observed with inhibitors of key DDR kinases, specifically ATR inhibitors (like tuvusertib) and ATM inhibitors.[5] This provides a rationale for combining agents that target different nodes within the complex DNA repair network.
• Chemotherapeutic Agents: Synergy was also noted with several classes of chemotherapy, including topoisomerase I inhibitors and temozolomide.[5] Most significantly, this potential was confirmed in vivo, where studies in tumor xenograft models showed that HRS-1167 enhanced the antitumor efficacy of the platinum-based chemotherapy agent carboplatin.[5]

The positive synergy data with carboplatin is of particular strategic importance. Because the primary limitation of combining first-generation PARP inhibitors with platinum agents is their overlapping myelosuppression, the preclinical demonstration that a highly PARP1-selective agent can safely and effectively combine with carboplatin provides a direct, evidence-based rationale for a core part of the clinical development strategy. It laid the groundwork for trials like NCT06719973, which was designed to evaluate M9466 (HRS-1167) in combination with carboplatin, reflecting a highly logical and data-driven progression from the laboratory to the clinic.[1]

Clinical Development Program

The clinical development program for HRS-1167 is ambitious and strategically designed to validate its core hypotheses of superior safety and broad efficacy. The program encompasses monotherapy and a range of rational combination studies across multiple solid tumor types where HRR deficiency is prevalent and PARP inhibition is a relevant therapeutic strategy.

Strategic Overview of the Clinical Portfolio

The portfolio of clinical trials for HRS-1167 reflects a multi-pronged strategy aimed at establishing its profile as a foundational DDR agent. The program is progressing from initial safety and monotherapy efficacy assessments in broad patient populations to more focused combination studies in specific indications like prostate, ovarian, and breast cancer. The withdrawal or suspension of some early combination studies under EMD Serono's sponsorship may indicate a strategic reprioritization or consolidation of the development plan following the licensing deal, a common occurrence in such transitions.

Table 1: Overview of the HRS-1167 Clinical Development Program

NCT Identifier	Phase	Title/Indication	Interventions	Sponsor(s)	Status	Source(s)
NCT05473624	1	Monotherapy in Advanced Solid Tumors	HRS-1167	Jiangsu Hengrui	Active, not recruiting	6
NCT06689163	1/2	Metastatic Prostate Cancer	HRS-1167 + Abiraterone + Prednisone	Jiangsu Hengrui	Recruiting	1
NCT06308406	1b/2	Recurrent Ovarian Cancer	HRS-1167 + Bevacizumab	Jiangsu Hengrui	Recruiting	11
NCT06516289	2	Neoadjuvant gBRCA-mutated HER2-Neg Breast Cancer	HRS-1167 + Famitinib ± Camrelizumab	Fudan University	Recruiting	10
NCT06719973	1	Advanced Solid Tumors (ES-SCLC focus)	M9466 (HRS-1167) + Carboplatin (+ Etoposide + Atezolizumab)	EMD Serono	Withdrawn	1
NCT06509906	1	Advanced Solid Tumors / Colorectal Cancer	M9466 (HRS-1167) + Topoisomerase I inhibitor-based regimens	EMD Serono	Suspended	1
NCT06198556	1	Drug-Drug Interaction Study (Healthy Volunteers)	HRS-1167 + Rifampicin	Jiangsu Hengrui	Completed	38

In-Depth Analysis: The First-in-Human Monotherapy Study (NCT05473624)

The most mature and impactful clinical data for HRS-1167 to date comes from the Phase 1 first-in-human study, NCT05473624. Results from this trial, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, provided the first clinical validation of the drug's potential.[6]

Study Design and Patient Population

NCT05473624 is an open-label, multicenter Phase 1 trial structured with dose-escalation (D-ESC) and dose-expansion (D-EXP) components.[6] The D-ESC portion was designed to establish the safety profile and identify a recommended dose, enrolling patients with advanced solid tumors who had progressed on standard therapies. It began with an accelerated titration design at 30 mg once daily (QD) and then switched to a Bayesian Optimal Interval (BOIN) design to evaluate doses of 50, 100, 200, and 300 mg QD.[6] The D-EXP part was designed to gather more robust efficacy and safety data in a targeted population, enrolling previously treated patients with tumors harboring documented germline or somatic mutations in HRR genes, specifically

BRCA1/2, PALB2, or RAD51C/D, at doses of 50, 100, and 200 mg QD.[6]

The patient population was characteristic of a Phase 1 oncology trial, being heavily pretreated with a median of 2 to 3 prior lines of therapy for metastatic disease.[6] Critically, prior treatment with a first-generation PARP inhibitor was permitted, with 15% of the overall population and up to 50% of one reported cohort having received prior PARPi therapy.[6] This inclusion criterion makes the subsequent efficacy results particularly compelling, as it suggests activity in a PARPi-experienced, and thus potentially resistant, setting.

Safety and Tolerability Profile

The primary objectives of the study were to assess the safety and tolerability of HRS-1167.[6] The results presented, based on a data cutoff of November 20, 2023, for 40 enrolled patients, were highly encouraging and supportive of the PARP1-selectivity hypothesis. No dose-limiting toxicities (DLTs) were observed across the dose levels tested up to 300 mg QD, and consequently, the maximum tolerated dose (MTD) was not reached.[6]

Treatment-related adverse events (TRAEs) of Grade 3 or higher occurred in 30.0% of patients (12 of 40).[6] The most frequent of these severe TRAEs were hematological, as expected for the drug class, but the rates were notably moderate. This profile is a key point of differentiation. While a direct, randomized comparison is not available, these initial rates appear favorable when compared to the rates of severe myelosuppression often reported in pivotal trials of first-generation dual PARP1/2 inhibitors, which can be a major cause of dose modifications and treatment burden for patients.

Table 2: Summary of Grade ≥3 Treatment-Related Adverse Events in NCT05473624 (n=40)

Adverse Event	Percentage of Patients (n=40)	Source(s)
Any Grade ≥3 TRAE	30.0%	6
Anemia	15.0%	6
Decreased Neutrophil Count	12.5%	6
Decreased WBC Count	12.5%	6

Pharmacokinetic (PK) and Pharmacodynamic (PD) Findings

The pharmacokinetic analysis demonstrated that HRS-1167 has a predictable and favorable profile. Drug exposures (as measured by Cmax​ and AUC) were found to be approximately dose-proportional across the 30 mg to 300 mg range.[6] Following a single oral dose, the drug was rapidly absorbed, with a median time to maximum concentration (

Tmax​) of 1.0 to 1.5 hours.[6] The mean elimination half-life (

t1/2​) was between 10.5 and 15.0 hours, supporting a once-daily dosing schedule.[6] Importantly, there was no evidence of significant drug accumulation upon multiple dosing, with accumulation ratios (

Rac​) for Cmax​ and AUC remaining low (1.08–1.30 and 1.29–1.62, respectively).[6] Pharmacodynamic assessments confirmed excellent target engagement in patients. At steady-state, PARylation inhibition in peripheral blood mononuclear cells was greater than 90%, indicating that HRS-1167 was effectively and continuously inhibiting its PARP1 target at the doses administered.[29]

Preliminary Clinical Efficacy

The most striking result from the NCT05473624 study was the promising signal of antitumor activity. Among the 24 patients with qualifying HRR mutations who had at least one post-baseline tumor assessment, 10 patients (41.7%) achieved a confirmed objective response.[6] This level of efficacy is exceptionally high for a Phase 1 dose-escalation study, particularly in such a heavily pretreated population. The responses were observed across a range of tumor types known to be sensitive to PARP inhibition, including 8 responses in ovarian cancer, 1 in prostate cancer, and 1 in pancreatic cancer.[6] This robust and early efficacy signal, especially in patients who may have already been exposed to a prior PARP inhibitor, provides strong clinical proof-of-concept for HRS-1167's potent single-agent activity and is a primary driver of the high level of enthusiasm for the asset.

Ongoing Combination Studies: Expanding the Therapeutic Horizon

Building on the strong monotherapy foundation, the clinical program is strategically exploring HRS-1167 in several rational combination regimens designed to address high unmet needs.

• NCT06689163 (Prostate Cancer): This Phase 1/2 study is evaluating HRS-1167 in combination with the standard-of-care androgen receptor pathway inhibitor (ARPI) abiraterone acetate (plus prednisone) in patients with metastatic prostate cancer.[1] This is a highly logical pairing, as there is a strong biological rationale and emerging clinical evidence for combining PARP inhibitors with ARPIs to treat HRR-mutated prostate cancer.
• NCT06308406 (Ovarian Cancer): This Phase 1b/2 trial combines HRS-1167 with the anti-angiogenic agent bevacizumab for patients with recurrent ovarian cancer.[11] This strategy builds directly upon the success of the landmark PAOLA-1 trial, which established the combination of a first-generation PARP inhibitor (olaparib) with bevacizumab as a highly effective first-line maintenance therapy for HRD-positive advanced ovarian cancer.[16] The central hypothesis is that the superior safety profile of HRS-1167 may improve the tolerability and, therefore, the overall benefit of this proven combination strategy.
• NCT06516289 (Breast Cancer): This investigator-sponsored Phase 2 trial represents a particularly innovative approach. It is evaluating a chemotherapy-free neoadjuvant regimen of HRS-1167 combined with famitinib (a multi-kinase inhibitor) for patients with germline BRCA-mutated, HER2-negative breast cancer.[10] A third arm may add the PD-1 inhibitor camrelizumab. This study aims to leverage the potent activity of HRS-1167 to move targeted therapy into an earlier, curative-intent setting, potentially sparing patients the toxicity of conventional neoadjuvant chemotherapy.

Strategic and Commercial Landscape

The development of HRS-1167 is not occurring in a vacuum but is instead a high-stakes endeavor within a dynamic and competitive segment of the oncology market. The strategic decisions made by its developers and the competitive context will be as crucial to its ultimate success as its clinical data.

The Jiangsu Hengrui and Merck KGaA Alliance

A pivotal event in the story of HRS-1167 was the announcement in October 2023 of a major strategic collaboration between the originator, Jiangsu Hengrui Pharmaceuticals, and the global biopharmaceutical company Merck KGaA, Darmstadt, Germany.[4] Under the terms of the agreement, Merck KGaA secured an exclusive license to develop, manufacture, and commercialize HRS-1167 in all global territories outside of mainland China.[4]

The financial terms of the deal are substantial and reflect a high degree of confidence in the asset's potential. Hengrui received an upfront payment of €160 million (approximately $169 million) and is eligible to receive additional payments tied to the achievement of specific development, regulatory, and commercial milestones, as well as tiered royalties on net sales. The potential total value of the deal for HRS-1167 could reach up to €1.4 billion (approximately $1.48 billion).[4]

For Hengrui, a leading pharmaceutical company in China, this agreement represents its first major strategic partnership with a global pharmaceutical giant and serves as a critical milestone in its efforts to globalize its innovative pipeline.[4] For Merck KGaA, the acquisition of HRS-1167 is a transformative move that aligns perfectly with its declared strategic focus on building a leading pipeline in the DNA Damage Response (DDR) field.[4] Prior to this deal, Merck KGaA had a smaller, earlier-stage interest in PARP1 inhibition through an option agreement with Nerviano Medical Sciences for their candidate, NMS-293.[19] By securing the rights to HRS-1167, a clinically validated asset with compelling Phase 1 efficacy and safety data, Merck KGaA effectively leapfrogged years of early-stage development. This aggressive business development maneuver immediately elevates them to a leading position in the race to develop a next-generation PARP1 inhibitor, placing them in direct competition with major players like AstraZeneca.

Competitive Positioning and Market Context

The market for PARP inhibitors is mature and competitive, but the distinct profile of HRS-1167 provides a clear path for differentiation.

Versus First-Generation PARP Inhibitors

HRS-1167's primary competitive advantage lies in its potential for a superior therapeutic index, driven by its high selectivity for PARP1. If pivotal trials confirm that this selectivity translates into a clinically meaningful reduction in hematological toxicities compared to dual PARP1/2 inhibitors like olaparib and niraparib, HRS-1167 could establish a new standard of safety and tolerability in the class. This would be a powerful differentiator for prescribing physicians and could lead to better patient compliance and the ability to maintain optimal dosing for longer periods. The early clinical data supports this hypothesis, suggesting lower rates of severe anemia and neutropenia than are typically seen with some first-generation agents.

Table 3: Comparative Profile of HRS-1167 and Select First-Generation PARP Inhibitors

Feature	HRS-1167 (M9466)	Olaparib	Niraparib
Target Selectivity	PARP1-selective (>672-fold vs PARP2) 5	Dual PARP1/2 12	Dual PARP1/2 12
Reported ORR (HRD+ Tumors)	41.7% (Ph 1, pretreated solid tumors) 6	Varies by trial/tumor type (e.g., ~31% in Ph2 BRCAm ovarian) 15	Varies by trial/tumor type (e.g., ~41% in gBRCAm ovarian) 13
Reported Grade ≥3 Anemia	15.0% (Ph 1) 6	~17-20% (in various studies) 15	~25-31% (in various studies) 13
Reported Grade ≥3 Thrombocytopenia	Not reported as a top event (likely <12.5%) 6	~3-5% (in various studies) 15	~29-34% (in various studies) 13
Reported Grade ≥3 Neutropenia	12.5% (Ph 1) 6	~4-9% (in various studies) 15	~20-30% (in various studies) 13

Note: Cross-trial comparisons should be interpreted with caution due to differences in patient populations, study designs, and lines of therapy.

Versus Other Next-Generation PARP1-Selective Inhibitors

HRS-1167 is a leading contender but not the only player in the emerging field of PARP1-selective inhibitors. The competitive landscape includes several other promising molecules, most notably from AstraZeneca, which has long been a leader in the PARP inhibitor space. AstraZeneca's portfolio includes saruparib (AZD5305), which has also shown impressive early efficacy and a favorable safety profile in clinical trials, and AZD9574, a brain-penetrant PARP1-selective inhibitor designed to treat central nervous system metastases.[12] Other companies, such as Gilead Sciences, have also entered the space through acquisitions.[19] The race to market among these next-generation agents will be intense, and success will likely depend on subtle but clinically meaningful differences in efficacy, safety, and the strategic execution of their respective clinical development programs.

Standard of Care Context

HRS-1167 will enter a market where first-generation PARP inhibitors are already entrenched as the standard of care in several key indications. For example, in first-line maintenance therapy for HRD-positive advanced ovarian cancer, olaparib (with or without bevacizumab) and niraparib are the established standards.[16] Similarly, olaparib and talazoparib are standards of care for patients with germline

BRCA-mutated metastatic breast cancer.[36] To gain market share, HRS-1167 will need to demonstrate not just non-inferiority but clear superiority, either in terms of efficacy, safety, or both, or by succeeding in patient populations where current agents are less effective or poorly tolerated.

Synthesis and Future Outlook

HRS-1167 has emerged as a highly promising, next-generation PARP1 inhibitor with a clear and compelling development narrative. By integrating the available preclinical, clinical, and strategic data, a comprehensive picture of its potential and the path forward becomes clear.

Integrated Assessment and Concluding Remarks

The evidence accumulated to date strongly supports the central hypothesis that HRS-1167 can achieve the goal of uncoupling PARP-mediated antitumor efficacy from PARP2-mediated hematological toxicity. Its profile is defined by three core strengths:

1. High Target Selectivity: The demonstrated 672-fold selectivity for PARP1 over PARP2 is the key molecular attribute that underpins its potential for an improved therapeutic index.[5]
2. Favorable Safety Profile: Early clinical data from the Phase 1 trial have substantiated this hypothesis, showing that HRS-1167 is well-tolerated with moderate rates of severe myelosuppression and no MTD reached at robustly active doses.[6]
3. Impressive Preliminary Efficacy: The 41.7% objective response rate observed in a heavily pretreated, HRR-mutated patient population is an exceptionally strong efficacy signal for a Phase 1 study and suggests potent single-agent activity, even in a potentially PARPi-resistant setting.[6]

Collectively, these attributes position HRS-1167 as a potential best-in-class PARP inhibitor. Its enhanced safety profile could not only improve the patient experience in existing indications but, more importantly, could unlock the full potential of PARP inhibition in combination therapies with myelosuppressive agents, significantly broadening its clinical utility.

Projected Development Trajectory and Unanswered Questions

The future development of HRS-1167 will be focused on translating its early promise into definitive clinical benefit in pivotal trials. The logical progression will involve advancing the most promising combination strategies from the ongoing Phase 1/2 studies into larger, randomized Phase 3 trials. These trials will likely be designed to demonstrate superiority over the current standard of care—which may include chemotherapy or a first-generation PARP inhibitor—in well-defined patient populations, such as first-line maintenance in HRD-positive ovarian cancer or in combination with an ARPI for HRR-mutated metastatic castration-resistant prostate cancer.

Despite the strong positive signals, several critical questions remain that must be addressed by future clinical data:

• Durability of Response and Survival Benefit: While the high ORR is encouraging, it is crucial to determine if these responses are durable and if they translate into a statistically significant and clinically meaningful improvement in Progression-Free Survival (PFS) and, ultimately, Overall Survival (OS) in randomized controlled trials.
• Long-Term Safety: The safety profile appears favorable in the short-term context of a Phase 1 study. Larger and longer-term studies will be needed to fully characterize the long-term safety profile and monitor for any cumulative or rare toxicities.
• Head-to-Head Superiority: To displace entrenched first-generation agents, HRS-1167 may ultimately need to demonstrate clear superiority in a head-to-head clinical trial, either on an efficacy or a safety and tolerability endpoint.
• Optimal Combination Strategies: The broad clinical program is exploring multiple combinations. A key challenge will be to identify which combinations provide the greatest synergistic benefit and in which specific molecularly-defined patient populations, thereby maximizing its impact.

In conclusion, HRS-1167 stands out as a leading example of rational, next-generation drug design in oncology. It possesses a strong scientific rationale, compelling preclinical data, and exceptionally promising early clinical results. With the powerful backing of the Merck KGaA and Jiangsu Hengrui alliance, it is well-positioned to advance rapidly through late-stage development. If the positive data continues to mature and the key questions above are answered favorably, HRS-1167 has the clear potential to become a new standard of care and a cornerstone therapy for a wide range of HRD-positive cancers.

Works cited

1. HRS-1167 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 12, 2025, https://synapse.patsnap.com/drug/392fd0ce0992424da5853f06fabd3909
2. Definition of PARP1 inhibitor HRS-1167 - NCI Drug Dictionary, accessed September 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/parp1-inhibitor-hrs-1167
3. M9466 / Jiangsu Hengrui Pharma, EMD Serono - LARVOL DELTA, accessed September 12, 2025, https://delta.larvol.com/Products/?ProductId=4f4e06c1-1a02-4aeb-9953-ca3dcaa58e3f
4. News Release Merck Strengthens Oncology Pipeline Through Strategic Partnership with Hengrui for Next- Generation Selective PARP1, accessed September 12, 2025, https://www.merckgroup.com/content/dam/web/corporate/non-images/press-releases/2023/oct/en/Hengrui-Oncology-Collaboration-EN.pdf
5. Abstract 1171: M9466 (HRS-1167): A highly potent and selective ..., accessed September 12, 2025, https://aacrjournals.org/cancerres/article/85/8_Supplement_1/1171/760941/Abstract-1171-M9466-HRS-1167-A-highly-potent-and
6. A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors., accessed September 12, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.3154
7. A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 ..., accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3154
8. A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors. | Request PDF - ResearchGate, accessed September 12, 2025, https://www.researchgate.net/publication/381968607_A_phase_1_study_of_HRS-1167_M9466_a_highly_selective_PARP1_inhibitor_in_patients_pts_with_advanced_solid_tumors
9. Merck KGaA forges strategic alliance with Hengrui to boost cancer pipeline, accessed September 12, 2025, https://firstwordpharma.com/story/5794963
10. Study Details | NCT06516289 | Neoadjuvant Treatment of gBRCA ..., accessed September 12, 2025, https://clinicaltrials.gov/study/NCT06516289
11. A Phase Ib/II Clinical Study of HRS-1167 in Combination With Bevacizumab in Patients With Recurrent Ovarian Cancer - TrialX, accessed September 12, 2025, https://www.trialx.com/clinical-trials/listings/287119/a-phase-ibii-clinical-study-of-hrs-1167-in-combination-with-bevacizumab-in-patients-with-recurrent-ovarian-cancer/
12. Leveraging PARP-1/2 to Target Distant Metastasis - MDPI, accessed September 12, 2025, https://www.mdpi.com/1422-0067/25/16/9032
13. PARP Inhibitors Have Acceptable Toxicity Profiles and Have Shown Efficacy in Treatment of Ovarian Cancer, accessed September 12, 2025, https://www.jons-online.com/womens-health-monthly-minutes/parp-inhibitors-have-acceptable-toxicity-profiles-and-have-shown-efficacy-in-treatment-of-ovarian-cancer
14. Targeting PARP1: A Promising Approach for Next-Generation Poly (ADP-ribose) Polymerase Inhibitors - PMC, accessed September 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12162764/
15. A Review of PARP Inhibitors in Clinical Development, accessed September 12, 2025, https://jhoponline.com/issue-archive/2012-issues/march-vol-2-no-1/top-14855
16. Ovarian Cancer HRD Testing – LYNPARZA® (olaparib) + Bevacizumab, accessed September 12, 2025, https://www.lynparzahcp.com/ovarian-cancer/testing/hrd-testing.html
17. Therapeutic advances and application of PARP inhibitors in breast ..., accessed September 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12142329/
18. Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305 - Frontiers, accessed September 12, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.979873/full
19. Merck pays $169M for selective PARP1 drug, stepping up challenge to AstraZeneca and Gilead - Fierce Biotech, accessed September 12, 2025, https://www.fiercebiotech.com/biotech/merck-pays-169m-selective-parp1-drug-stepping-challenge-astrazeneca-and-gilead
20. Abstract 4562: Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination - AACR Journals, accessed September 12, 2025, https://aacrjournals.org/cancerres/article/84/6_Supplement/4562/737930/Abstract-4562-Activity-of-PARP1-selective
21. AACR: PARP1-selective inhibitor demonstrates early efficacy in breast cancers with DNA repair defects, accessed September 12, 2025, https://www.mdanderson.org/newsroom/aacr--parp1-selective-inhibitor-demonstrates-early-efficacy-breast-cancers-DNA-repair-defects.h00-159696756.html
22. Patent Analysis of Jiangsu Hengrui's PARP1 Inhibitor HRS-1167 - Patsnap Synapse, accessed September 12, 2025, https://synapse.patsnap.com/blog/patent-analysis-of-jiangsu-hengruis-parp1-inhibitor-hrs-1167
23. K-RAS (Sibylla) - Drug Targets, Indications, Patents - Synapse, accessed September 12, 2025, https://synapse-patsnap-com.libproxy1.nus.edu.sg/drug/60e7ffef18644587aa186e9aab0a5469
24. www.cancer.gov, accessed September 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/parp1-inhibitor-hrs-1167#:~:text=Upon%20oral%20administration%2C%20PARP1%20inhibitor,excision%20repair%20(BER)%20pathway.
25. Hengrui Pharma Partners with Merck KGaA, Darmstadt, Germany, to Advance Innovative Cancer Therapies - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/news-releases/hengrui-pharma-partners-with-merck-kgaa-darmstadt-germany-to-advance-innovative-cancer-therapies-301970919.html
26. Study Details | NCT06719973 | Phase 1 Study of M9466 Combined ..., accessed September 12, 2025, https://clinicaltrials.gov/study/NCT06719973
27. A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors. - ASCO Meeting Program Guide, accessed September 12, 2025, https://meetings.asco.org/abstracts-presentations/234086
28. NCT05473624 | Study of HRS-1167 as Monotherapy in Patients With Advanced Solid Tumors | ClinicalTrials.gov, accessed September 12, 2025, https://clinicaltrials.gov/study/NCT05473624
29. The efficacy and safety of a selective PARP1 inhibitor ACE-86225106 in patients with advanced solid tumors: Preliminary results from a first-in-human phase 1/2 study. - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3153
30. Ovarian Cancer Recurrent Recruiting Phase 1 / 2 Trials for Bevacizumab (DB00112), accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0047223/clinical_trials/DB00112?phase=1%2C2&status=recruiting
31. Merck partners with Hengrui in deal worth up to $1.48bn - Pharmaceutical Technology, accessed September 12, 2025, https://www.pharmaceutical-technology.com/news/merck-partners-with-hengrui-in-deal-worth-up-to-1-48bn/
32. Cooley Supports Jiangsu Hengrui in Two Global License Agreements, accessed September 12, 2025, https://www.cooley.com/news/coverage/2023/2023-11-08-cooley-supports-jiangsu-hengrui-in-two-global-license-agreements
33. Merck KGaA takes another shot at PARP1 | ApexOnco - Oncology Pipeline, accessed September 12, 2025, https://www.oncologypipeline.com/apexonco/merck-kgaa-takes-another-shot-parp1
34. Next-Generation PARP1-Selective Inhibitor Offers Significant Benefits Over Older Predecessors in Treatment of Solid Tumors - The ASCO Post, accessed September 12, 2025, https://ascopost.com/issues/may-25-2022/parp1-selective-inhibitor-offers-significant-benefits-over-older-predecessors-in-treatment-of-solid-tumors/
35. Homologous recombination deficiency - Target Ovarian Cancer, accessed September 12, 2025, https://targetovariancancer.org.uk/about-ovarian-cancer/genetic-genomic-testing/homologous-recombination-deficiency
36. Inherited BRCA mutations | Living Beyond Breast Cancer, accessed September 12, 2025, https://www.lbbc.org/about-breast-cancer/testing/genetic/brca
37. Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.23.02225
38. Study Details | NCT06198556 | Effect of Rifampicin on the Pharmacokinetics of HRS-1167 in Healthy Subjects | ClinicalTrials.gov, accessed September 12, 2025, https://clinicaltrials.gov/study/NCT06198556
39. HRS-1167 Completed Phase 1 Trials for Advanced Solid Tumors, accessed September 12, 2025, https://go.drugbank.com/drugs/DB18703/clinical_trials?conditions=DBCOND0030110&phase=1&purpose=treatment&status=completed