Introduction

Poly(ADP-ribose) polymerases (PARPs) play a crucial role in DNA repair by catalyzing the transfer of ADP-ribose units from NAD+ to specific target proteins. Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of drugs that selectively target and eliminate cancer cells with impaired homologous recombination-mediated DNA repair mechanisms by blocking PARP.1 PARPis induce apoptosis in tumor cells by disrupting DNA repair pathways, and they have displayed significant therapeutic efficacy against solid tumors.2 Four PARPis, namely olaparib,3 niraparib,4 rucaparib,5 and talazoparib,6 have received approval for use in the United States and Europe,7 whereas fuzuloparib and pamiparib were recently approved in China. Nonetheless, there are several challenges pertaining to the clinical application of these drugs, such as the assessment of long-term survival benefits, optimization of the mechanisms of action, and management of adverse effects.

In the SOLO-17 and SOLO-2 trials,8,9 olaparib produced a significant overall survival (OS) benefit as a maintenance therapy for patients with ovarian cancer. Whereas other PARPis have significantly extended progression-free survival (PFS) in patients with BRCA-mutated or homologous recombination deficiency (HRD)-positive cancer—particularly ovarian, breast, pancreatic, and prostate cancers—the improvements in OS were not statistically significant in the clinical trials. Meanwhile, some studies reported the detrimental effects of certain PARPis on OS in patients with cancer. For instance, the SOLO-3 confirmatory Phase III study reported a 33% reduction in OS among patients who were treated with olaparib after three or more lines of chemotherapy compared to patients who only received chemotherapy.10 Similarly, in the ARIEL-4 study, the OS rate among patients treated with rucaparib after two or more lines of chemotherapy was 31.3% lower than that among patients in the chemotherapy arm.10 These findings call for a deeper assessment of the mechanisms influencing long-term survival risk within this subpopulation of patients.

Apart from directly inhibiting PARP activity and stalling the repair of single-strand breaks, PARPis form and stabilize PARP–DNA complexes at single-strand break sites, thereby obstructing DNA repair and leading to the formation and accumulation of lethal double-strand breaks.11 These “trapped” PARP–DNA complexes disrupt DNA replication, resulting in greater cytotoxicity compared with that induced by direct PARP inhibition. Although all PARPis can effectively and selectively inhibit PARPs, particularly PARP1 and PARP2, there is considerable heterogeneity in their pharmacological and pharmacokinetic characteristics. Talazoparib, the most cytotoxic PARPi known at present, exhibits approximately 100-fold greater potency in promoting PARP–DNA complex formation compared to olaparib and rucaparib, and nearly 1,000-fold greater potency compared with veliparib, a PARPi currently in development. Although talazoparib and olaparib exert similar inhibitory effects on the catalytic activity of PARP,12 the significant cytotoxicity of talazoparib has led to its consideration as a second-generation PARPi. In fact, the recommended dosage of talazoparib (1 mg per day) is significantly lower than those of olaparib (300 mg BID), rucaparib (600 mg BID), and niraparib (200 or 300 mg per day, depending on the indication). Notably, niraparib is the sole PARPi for which dose reduction is advised in patients with hepatic impairment,13 whereas talazoparib and olaparib require dose adjustments in patients with renal impairment.14,15 Furthermore, the unique metabolic pathways associated with individual PARPis affect drug interactions. Olaparib is primarily metabolized by CYP3A4/5, whereas rucaparib is mainly metabolized by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Niraparib is predominantly metabolized by carboxylate esterases, and talazoparib undergoes minimal hepatic metabolism. Consequently, talazoparib carries a low likelihood of drug–drug interactions.

It is crucial to develop novel PARPis with reduced adverse effects and enhanced tumor-suppressive abilities to improve the long-term survival outcomes in patients.

HWH340 is a PARPi developed by the Hubei Biomedical Industry and Technology Research Institute Co., Ltd. for the treatment of solid tumors harboring BRCA mutations/deletions or PARP overexpression, including ovarian, breast, pancreatic, and small cell lung cancers. It can be administered as a monotherapy or in combination with chemotherapy and radiotherapy. According to unpublished data in the HWH340 Investigator’s Brochure, in vitro enzymatic and cellular activity assays have demonstrated significant selectivity and potent inhibitory effects of HWH340 against its pharmacodynamic targets, with PARP1 inhibition and cytotoxicity comparable to that of olaparib. Compared to veliparib, HWH340 showed five-fold greater activity against BRCA-mutated breast cancer MDA-MB-436 cells and displayed a slightly superior synergistic effect when combined with temozolomide (TMZ). Conversely, HWH340 and veliparib exhibited comparable activity against wild-type breast cancer MDA-MB-231 cells, and neither agent showed synergistic effects with TMZ. In these unpublished data from the Investigator’s Brochure on nonclinical evaluation in in vivo models, HWH340 monotherapy administered at 12.5 mg/kg BID in a BRCA1-mutated MDA-MB-436 xenograft model demonstrated superior preliminary anti-tumor activity compared to the same dose and regimen of veliparib, with dose-dependent tumor growth inhibition (TGI) rates of 130% and 64%, respectively. In a BRCA2-mutated human pancreatic cancer CAPAN-1 xenograft model, HWH340 monotherapy at 25 mg/kg achieved a TGI rate of 43.9%, compared to 10.95% and 16.89% for equivalent doses of veliparib and olaparib, respectively. When combined with 30 mg/kg TMZ, HWH340 at 25 mg/kg yielded a TGI rate of 79.61%, compared to 46.05% and 58.21% observed for the veliparib and olaparib groups, respectively. Therefore, both HWH340 monotherapy and its combination with TMZ showed slightly superior efficacy relative to equivalent doses of competing comparator PARPis. Furthermore, in the high PARP-expressing patient-derived xenograft small cell lung cancer model LU-01-0547, HWH340 monotherapy at 50 mg/kg QD achieved a TGI rate of 81.69%, compared to 53.22% for veliparib (50 mg/kg, BID) and 21.13% for olaparib (50 mg/kg, QD), again demonstrating marginally better efficacy.

Structurally, HWH340 is a potent PARPi with a distinct chemical framework that confers improved selectivity for PARP1/2 relative to earlier-generation agents. Additionally, HWH340 presents a highly favorable pharmacokinetic profile, including good oral bioavailability, which may translate to therapeutic benefits.

Although germline BRCA1/2 mutations represent the most well-characterized homologous recombination repair (HRR) defects with established sensitivity to PARP inhibition, other HRR gene alterations—including those in PALB2, RAD51C/D, ATM, and various somatic HRR genes—exhibit variable degrees of PARPi responsiveness depending on the underlying mechanism of HRR dysfunction. Therefore, we enrolled patients with any HRR gene mutation, not limited exclusively to BRCA mutations, during the dose-expansion phase of this study. The study has the following objectives: (1) to assess the safety and tolerability of HWH340 and determine the recommended phase 2 dose (RP2D); (2) to characterize the pharmacokinetic profile of HWH340; and (3) to explore preliminary anti-tumor activity across different HRR mutation subgroups to generate hypotheses for future efficacy-driven trials.

Materials and Methods Study Participants

The trial was open to patients aged 18–70 years with advanced solid tumors that were recalcitrant to standard therapies or lacked a suitable standard alternative. Other significant criteria were as follows: 1) expected survival ≥ 6 months; 2) no significant impairment of the hematopoietic system; 3) functional indices of the bone marrow, heart, lungs, liver, and kidneys within normal ranges; 4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; and 5) at least one measurable tumor according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Full eligibility criteria are detailed in Methods S1 in the Supplementary Information.

Study Design

This Phase I, open-label, multicenter, three-part study was conducted across 25 centers in China under the leadership of the Tianjin Medical University Cancer Institute and Hospital.

The dose-escalation phase followed a standard “3 + 3” design. All patients in this initial phase were recruited from the Tianjin Cancer Institute and Hospital to evaluate the safety, tolerability, and pharmacokinetic properties of the drug. The starting dose for the single-dose study, 20 mg, was determined based on preclinical toxicologic, pharmacodynamic, and non-clinical pharmacokinetic data and the results of phase 1 clinical studies on similar drugs. The maximum dose was determined to be 520 mg based on the results of animal toxicology testing. Doses of 20, 60, 120, 200, 280, 400, and 520 mg were sequentially tested (n=3 per dose group) until the maximum dose or maximum tolerated dose (MTD) was reached.

After completing treatment in the 400-mg dose group, a multiple-dose study was concurrently initiated with the next single-dose group. The initial treatment cycle consisted of two doses of 100 mg daily. After assessing the safety data, the doses were increased to 140 and 200 mg BID. The decision to initiate multiple doses of 260 mg was based on the tolerability of the single 520-mg dose. Patients were subjected to 28-day cycles of multiple dosing phases (days 1–28) and subsequent treatment phases until definite disease progression, intolerable study drug-related adverse events (AEs), initiation of other antineoplastic therapy, death, withdrawal of informed consent, or loss to follow-up.

The objectives of the dose-expansion study were to evaluate the preliminary anti-tumor activity, safety, and tolerability of HWH340 tablets and to determine the RP2D. The RP2D selection aligns with contemporary dose-optimization frameworks, which advocate for integrating safety, PK, and activity data rather than relying solely on MTD-based approaches. Two dosages (140 mg and 200 mg orally BID) were selected for the dose-expansion phase based on the safety, pharmacokinetic results, and preliminary anti-tumor efficacy observed in the multiple-dose escalation phase cohorts. Each dose group comprised 20 patients, with 50% harboring germline and/or somatic BRCA1/2 mutations, and the remaining 50% testing positive for mutations in HRR-related genes other than BRCA1/2.

In cycle 1, the ECOG performance status was calculated, followed by an electrocardiogram (ECG) and a safety assessment on day 1; safety assessments were repeated on days 14 and 28. In cycle 2, safety was assessed on day 14, and a safety assessment, imaging, and tumor marker analysis were conducted on day 28. In cycles 3–6, safety was assessed on day 28, with imaging and tumor marker analyses conducted on day 28 of even-numbered cycles. In subsequent cycles (after cycle 6), safety assessments, imaging, and tumor marker analyses were conducted during even-numbered cycles.

Endpoints

The primary endpoints were the MTD and RP2D of HWH340 tablets in patients with advanced solid tumors, with a particular focus on cohorts harboring HRR-related mutations.

The secondary endpoints were as follows: 1) objective response rate (ORR), defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as the best overall response; 2) disease control rate (DCR), defined as the proportion of patients with CR, PR, or stable disease (SD) according to RECIST version 1.1;16 3) duration of response (DOR); and 4) PFS. In addition, biomarkers related to the preliminary anti-tumor activity were also analyzed.

Pharmacokinetic Evaluations

Blood samples were collected from all patients in the dose-escalation study for pharmacokinetic analysis and identification of drug metabolites. Non-compartmental analysis was conducted using WinNonlin Phoenix (version 8.3; Pharsight, Certara Company, Radnor, PA, USA). Pharmacokinetic parameters, including the maximum plasma concentration (Cmax), time to the maximum plasma concentration (tmax), area under the concentration–time curve (AUC), clearance, and half-life, were determined to develop a pharmacokinetic model supporting optimal dose selection.

Safety Assessments

The MTD was determined as follows: If one subject in a dose group developed a dose-limiting toxicity (DLT), then three additional subjects were added to that dose group. If one additional case of DLT occurred in the three expanded subjects, then the trial was terminated, with the preceding dose of the treatment in question considered as the MTD. Conversely, in the absence of any further instances of DLT, the subsequent dose group was considered. If two subjects in the initial dose group developed DLT, the trial was terminated, and the preceding dose was considered the MTD. The dose was then increased in the designated dose groups until the MTD was identified or until the maximum dose (520 mg in this study) was reached.

DLT was defined as any of the following: 1) grade 4 hematologic toxic reactions; 2) grade 3 febrile neutropenia (neutrophil count < 1,000/mm3 with a single temperature reading exceeding 38.3°C or temperature ≥ 38°C for more than 1 h; 3) grade 3 thrombocytopenia with clinically significant hemorrhage or the need for platelet transfusion; 4) grade 3 and higher non-hematologic toxic reactions, excluding abnormalities in ALP and γ-glutamyltransferase; and 5) death or any other toxic reaction was identified by the investigator.

The observation period for DLT was as follows: For the single-dose study, from when the initial dose was administered until the conclusion of the safety assessment on day 7 post-administration; and for the multiple-dose study, from when the initial dose was administered until the conclusion of the multiple dosing phase.

Quantification and Statistical Analysis

There was no hypothesis testing for the Phase I study. The statistical analyses were descriptive and exploratory.

The full analysis set (FAS) included all subjects who received the study drug at least once and for whom post-dosing evaluation data were available. Compliance with the per-protocol set (PPS) included all patients who adhered to the enrollment criteria stated in the trial protocol, completed all scheduled visits, and did not use any prohibited medication or treatment during the trial period that could have affected the evaluation of efficacy of the study drug. The safety set (SS) included all subjects who used the study drug at least once and for whom post-dosing safety evaluation data were available. The pharmacokinetic analysis dataset included all subjects who used the study drug at least once and for whom post-dosing pharmacokinetic evaluation data were available. The dose determination dataset (DDS) included all patients in the SS who completed the minimum exposure requirements (received a minimum of 75% of the scheduled dose) and received an adequate safety evaluation or experienced a DLT during cycle 1 of the single- or multiple-dose study. The DDS was employed to assess DLTs.

The severity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.17 The preliminary anti-tumor activity of the treatment in subjects who received multiple doses of the drug was evaluated based on an overall assessment of the tumor according to the RECIST v1.1 criteria.16

Plasma concentrations of HWH340 and its metabolite HWH340-M8 were determined using a validated LC-MS/MS method. The method was thoroughly validated in accordance with regulatory guidelines, with assessments covering selectivity, precision, accuracy, matrix effect, recovery, carryover, dilution integrity, and stability. Incurred sample reanalysis was performed on 94 of the 564 plasma samples, of which 92 (97.9%) met the acceptance criteria. All reanalyzed results complied with the regulatory requirement that at least two-thirds of the re-assayed samples deviate by within ±20% of the original values.

Results Dose-Escalation Study Patient Characteristics

Twenty-one patients were enrolled in the single-dose study from March 5, 2018, to January 8, 2019, with three cases per dose group (Figure 1A). The age range of the 21 subjects included in the FAS was 33–69 years, and their body mass index (BMI) ranged from 17.1 to 30.9 kg/m2. The demographic information of the subjects is summarized in Table S1.

Figure 1 Flowchart of the study design. (A) In the single-dose escalation phase, oral doses were increased incrementally from 20 to 520 mg until the maximum dose or maximum tolerated limit was reached. (B) Following the single-dose trial, upon successful completion and safety clearance of the 400-mg group, the multiple-dose escalation phase was initiated at a starting dose of 100 mg Bid. The dose was then escalated to 140 and 200 mg BID. Entry into the 260-mg group was based on the safety results from the 520-mg single-dose trial. (C) In the dose-expansion phase, doses of 140 and 200 mg, taken orally BID, were selected according to the safety, pharmacokinetic, and preliminary antitumor efficacy profiles from the multiple-dose escalation trial. BID, twice daily.

Fourteen patients were enrolled in the multiple-dose study from December 10, 2018, to February 10, 2022 (Figure 1B). Twelve of the patients included in the PPS completed the study; the remaining two patients were automatically withdrawn from the trial (Figure S1). The age range of the 14 subjects included in the FAS was 48–69 years, and the BMI range was 18.5–30.9 kg/m2. The demographic information of the subjects is summarized in Table S2.

Safety

In the single-dose phase, all subjects received 100% of the intended dose. Fourteen patients were enrolled in the multiple-dose phase, of whom 12 received 100% of the intended dose. The remaining two patients discontinued early due to personal reasons unrelated to AEs or treatment-related intolerance. No DLT was observed in any dose group, and no MTD was identified in the single-dose or multiple-dose study. In addition, none of the AEs led to fatalities or withdrawal in any dose group during the trial.

In the single-dose study, 73 AEs were reported in 19 of 21 participants included in the SS. The AE incidence rate was 90.5%, and all events were treatment-emergent AEs (TEAEs). In addition, 61 AEs in 18 subjects were considered potentially related to HWH340 and were thus categorized as adverse reactions, corresponding to an incidence rate of 85.7%. Two AEs were classified as grade 3 in severity, including one case of γ-glutamyltransferase elevation and one instance of neutropenia. The remaining AEs were classified as either grade 1 or 2 in severity. Excluding nausea, which occurred predominantly in the 400- and 520-mg dose groups, none of the AEs with an incidence greater than 10% was significantly dose-related. The AEs in the single-dose trial are summarized in Table S3.

In the multiple-dose study, 170 TEAEs were observed in all 14 participants included in the SS, and 164 AEs were identified as adverse reactions. The incidence rates of TEAEs and adverse reactions were both 100%. One subject experienced a serious adverse event (SAE) characterized by a grade 3 rash. Only rash and neutropenia were classified as grade 3 in severity, whereas most AEs were classified as grade 1 or 2. The adverse reactions with incidence rates of ≥20% (Table 1) included elevated blood creatinine levels (71.4%), hypoalbuminemia (57.1%), leukopenia (57.1%), anemia (57.1%), prolonged QT interval on ECG (42.9%), ST-T segment changes on ECG (42.9%), neutropenia (35.7%), nausea (35.7%), elevated alanine aminotransferase levels (28.6%), elevated aspartate aminotransferase levels (28.6%), vomiting (28.6%), fever (21.4%), and thrombocytopenia (21.4%). Excluding nausea and vomiting, which occurred predominantly in the 200- and 260-mg dose groups, none of the AEs with an incidence greater than 10% was significantly dose-related. The adverse reactions in the multiple-dose trial are summarized in Table S4.

Table 1 Adverse Reactions of Any Grade (≥20%) in the Multiple-Dose Study

The AEs observed in the single-dose and multiple-dose studies were comparable to those reported for other PARPis. However, the incidence of neutropenia and leukopenia, anemia, γ-glutamyltransferase elevation, prolonged electrocardiographic QT interval, altered electrocardiographic ST-T segment, and nausea were higher in the present cohort. Overall, these findings indicate that oral HWH340 has acceptable safety and tolerability in patients with advanced solid tumors.

Pharmacokinetics

Single doses of HWH340 ranging from 20 to 520 mg were taken orally in the form of tablets. The median tmax of the drug ranged from 1.995 to 3.002 h, and the mean half-life ranged from 3.906 to 6.786 h. The coefficient of variation (CV) for Cmax ranged from 5.3% to 55.8%, whereas that for the AUC from zero to infinity (AUC0-∞) ranged from 10.4% to 64.3%. Both Cmax and AUC increased proportionately to the administered dose within the 20–520-mg dose range. These results are summarized in Table S5.

For the multiple-dose trial, HWH340 doses of 100, 140, 200, and 260 mg were administered BID over a 28-day period. Steady-state blood concentrations were achieved by day 26. The mean Cmax values for the doses of HWH340 on day 28 were 395, 1,140, 1,260, and 1,430 ng/mL, respectively, and the mean AUCs at steady state (AUCss,12h) were 3,260.612, 10,353.362, 11,638.465, and 11,855.113 ng·h/mL, respectively. Both Cmax and AUCss,12h tended to increase with increasing doses. On day 28, the mean accumulation ratios (Racc) for the respective doses of HWH340 over the 12-hour dosing interval (AUC0-12h) were 3.579, 3.288, 3.312, and 2.654. The results are summarized in Table 2.

Table 2 Pharmacokinetic Parameters of Each Multiple-Dose Group

Preliminary Anti-Tumor Activity

The therapeutic efficacy of HWH340 tablets in patients with advanced solid tumors was preliminarily assessed in the multiple-dose study. Fourteen participants were enrolled, and eight subjects underwent a comprehensive evaluation. Although the selected patients were not the optimal beneficiary population for HWH340 treatment because of the absence of mutations in HRR-related genes, one subject demonstrated PR, and five subjects achieved SD. The optimal total remission in each dosage group is presented as a waterfall plot in Figure S2. The ORRs in the FAS and PPS were 7.1% and 8.3%, respectively, and the DCRs in these sets were 42.9% and 50%, respectively.

In addition, a PR was noted in one subject in the 260-mg dosage cohort, resulting in ORRs of 25% and 33.3% in the FAS and PPS, respectively. Furthermore, the duration of remission in the 260-mg dosage group was 16.72 months. The best overall response was SD for one patient in the 100-mg group, three patients in the 140-mg group, and one patient in the 200-mg group. The DCRs for the FAS in the 100-, 140-, and 200-mg groups were 33.3%, 100%, and 25%, respectively, whereas the DCRs for these groups in the PPS were 33%, 100%, and 33.3%, respectively. The details are summarized in Tables S6 and S7.

Dose-Expansion Study Patient Characteristics

In total, 390 subjects with advanced solid tumors were screened for the dose-expansion study between August 17, 2020, and October 14, 2022. Forty-two individuals with HRD-related gene mutations were enrolled into the 140- or 200-mg dose group (Figure 1C), and the remaining 348 subjects were excluded. Group 1 consisted of patients with BRCA1/2 gene mutations, whereas patients in Group 2 harbored mutations in HRD-related genes other than BRCA1/2. Of the 42 subjects in the dose-expansion phase, 42 were included in the FAS, 41 in the PPS, and 42 in the SS (Figure 2).

Figure 2 Flowchart of the dose-expansion study.

All enrolled patients had received prior antitumor therapy. The demographic characteristics of the dose-related and mutation-related subgroups were similar (Table S8). The cancer diagnosis histories of patients in each dosage group are summarized in Table 3. Specifically, 23 subjects were diagnosed with breast cancer (including one with endometrial cancer), and 12 were diagnosed with ovarian cancer (including one with multiple pelvic metastases). The remaining subjects were diagnosed with various cancer types, including lung cancer (n = 1), pancreatic cancer (n = 2), rectal cancer (n = 1), gastric cancer (n = 1), pelvic mucinous liposarcoma (n = 1), and fallopian tube cancer (n = 1). The mutations detected in each subject are described in Table S9.

Table 3 Cancer Diagnosis History of Patients in the Dose-Expansion Study

Safety

Overall, 575 AEs were reported among the 42 subjects included in the SS, all of whom experienced TEAEs. Furthermore, 23.8% (10/42) of the subjects experienced SAEs, 50% (21/42) experienced grade 3 or higher AEs, and 11.9% (5/42) experienced AEs that led to withdrawal from the trial. Furthermore, 507 AEs were deemed definitely, likely, or possibly related to the test drug and were classified as adverse reactions. The results are summarized in Table S10.

Three participants experienced AEs during the trial that resulted in death. The cause of death for one subject in the 140-mg dose group could not be determined, and it was evaluated as possibly unrelated to the study drug. In addition, one subject in the 200-mg dose group died following renal failure, which was evaluated as possibly unrelated to the study drug. Another subject in the 200-mg dose group experienced paralytic intestinal obstruction that progressed to death, which was evaluated as possibly related to the study drug.

Subject K1205, a 66-year-old woman with advanced breast cancer, was enrolled in the 140-mg dose group, and treatment commenced on March 24, 2021. She received her last dose on June 8, 2021, and voluntarily withdrew from the study on June 21, 2021. During follow-up, her family informed the research team via telephone that she had died in October 2021. The precise cause of death could not be ascertained; however, it was preceded by multiple body aches and pains, likely attributable to disease progression. Given the advanced stage of the tumor, the short duration of expected survival, and the fact that the patient’s condition and regression were consistent with the characteristics of the disease, it was concluded that the AE was likely unrelated to the study drug.

Subject K2107, a 47-year-old woman with pancreatic cancer and metastases to the peritoneum, ovaries, and liver, commenced a 200-mg dosage regimen on April 30, 2021. On May 19, 2021, she experienced a grade 2 AE characterized by incomplete intestinal obstruction, which was potentially associated with the study drug, leading to its discontinuation. On May 24, 2021, she was diagnosed with complete intestinal obstruction, which necessitated extended hospitalization and resulted in paralytic intestinal obstruction (bowel obstruction). This SAE was attributed to multiple metastases within the abdominal cavity, possibly linked to disease progression and the study medication. On the same day, she was removed from the study group to receive symptomatic treatment. The subject died on June 26, 2021, and her death was possibly related to the paralytic intestinal obstruction, disease progression, and the study drug.

Subject K2109, a 61-year-old woman with advanced breast cancer, was enrolled in the 200-mg dose group on May 10, 2021. She was withdrawn from the group on June 21, 2021, because of a decreased platelet count. On July 19, 2021, she was diagnosed with renal failure, and dialysis was initiated. Given that this SAE occurred more than five half-lives after discontinuation of the study drug, and considering the pre-existing abnormal urinary proteins and occult blood detected before her enrollment, the renal damage most likely occurred prior to the drug regimen. Further evaluation with whole-abdomen spiral CT indicated persistent renal function impairment, possibly caused by urologic obstruction from tumor compression. The subject died on September 10, 2021, and the cause of death was attributed to multiorgan failure. It was concluded that the SAE of renal failure was not related to the study drug.

Adverse reactions with incidence rates exceeding 10% are listed in Table 4. The most prevalent hematologic adverse reactions were leukopenia (57.1%), anemia (40.5%), neutropenia (40.5%), and thrombocytopenia (23.8%). The most frequent non-hematologic adverse reactions included nausea (45.2%), vomiting (33.3%), elevated alanine aminotransferase levels (21.4%), and elevated aspartate aminotransferase levels (19%).

Table 4 Most Common Adverse Reactions (>10%, Any Grade) at Different Dose Levels

Of the 42 subjects included in the dose-expansion study, 20 subjects experienced grade 3 or higher adverse reactions, giving an incidence rate of 47.6%. The most common severe AEs (grade 3 and higher; Table 5) were neutropenia (14.3%), anemia (14.3%), vomiting (11.9%), leukopenia (9.5%), thrombocytopenia (4.8%), and elevated γ-glutamyltransferase levels (4.8%). The frequency of adverse reactions, including SAEs and grade 3 or higher AEs, was greater in the cohort receiving the 200-mg dosage (54.5%) than in the cohort receiving the 140-mg dosage (40%).

Table 5 Summary of the Adverse Reactions of Grade 3 or Higher in the Dose-Expansion Study

Notably, QT interval prolongation was detected in four patients during the study period. Two of these cases were classified as grade 1, one was classified as grade 2, and one was classified as grade 3. Such occurrences are relatively uncommon with other drugs of the same class; thus, careful consideration is warranted in future research.

Preliminary Anti-Tumor Activity

Among the 42 patients enrolled in the study, one patient achieved CR, seven patients achieved PR, and 16 patients exhibited SD, which was subsequently confirmed in 15 of these patients in the PPS. The ORR was 19% in the FAS, versus 19.5% in the PPS. The waterfall plot of the best overall response in 40 patients (two patients with censored data) is presented in Figure 3. The median DOR was 4.68 months. The DCRs were 57.1% and 56.1% for the FAS and PPS, respectively, with median PFS times of 3.65 and 3.61 months, respectively.

Figure 3 Change in tumor size in the dose-expansion study. This waterfall plot illustrates the best percentage change in the sum of the diameters of the target lesions (long axis for non-nodal lesions; short axis for nodal lesions) from baseline in patients treated with HWH340.

Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease.

The 200-mg dose demonstrated better preliminary anti-tumor activity than that of 140 mg. Within the 140-mg dose group (n=20), one patient achieved PR, and nine patients achieved SD, resulting in an ORR of 5% in both the FAS and PPS. The median DOR was 12.85 months, the DCR was 50%, and the median PFS was 2.43 months. In the 200-mg dose group (n=22 in the FAS; n=21 in the PPS), one patient achieved CR, six patients achieved PR, and seven patients exhibited SD (six in the PPS), yielding ORRs of 31.8% and 33.3% for the FAS and PPS, respectively. The median DOR was 3.71 months, the DCRs in the FAS and PPS were 63.6% and 61.9%, respectively, and median PFS was 4.07 months.

Group 1 exhibited better outcomes than Group 2. In the 140-mg dose cohort, Group 1 achieved an ORR of 10% in both the FAS and PPS, as well as a DCR of 60% and median PFS of 3.38 months. By contrast, the ORR of Group 2 patients was 0% in both the FAS and PPS for the same dose, the DCR was 40%, and the median PFS was 1.84 months. In the 200-mg dose cohort, Group 1 demonstrated an ORR of 41.7% in both the FAS and PPS, the DCR was 75%, and the median PFS was 4.44 months. Conversely, Group 2 exhibited ORRs of 20% and 22.2% in the FAS and PPS, respectively, with corresponding DCRs of 50% and 44.4%, respectively, and median PFS times of 3.61 and 1.84 months, respectively.

When stratified by tumor type, CR or PR was exclusively observed in patients with breast and ovarian cancer. In the PPS, the ORRs for patients with breast cancer in Groups 1 and 2 receiving the 140-mg dose were 14.3% and 0%, respectively, and the DCRs were 57.1% and 50%, respectively. In addition, the median PFS times in Groups 1 and 2 were 3.52 and 1.84 months, respectively. For patients receiving the 200-mg dose, the ORR was 50% in both groups, the DCR was 66.7% in both groups, and the median PFS times were 3.89 and 3.65 months, respectively. Patients with ovarian cancer receiving the 140-mg dose had an ORR of 0% in both groups, the DCRs were 66.7% and 0%, respectively, and the median PFS times were 3.25 and 1.82 months, respectively. In the 200-mg dose group, the ORRs for ovarian cancer patients were 40% and 0% in Groups 1 and 2, respectively, and the DCR was 100% in both groups. The median PFS times in these groups were 7.15 and 3.61 months, respectively.

Given the preliminary nature of these data, the observed anti-tumor activity should be viewed as hypothesis-generating, requiring validation in larger, well-powered studies.

Discussion

This study represents the first-in-human trial of HWH340, a PARP1/2 inhibitor characterized by high selectivity and potent enzymatic inhibitory activity in preclinical models. Single doses ranging from 20 to 520 mg and multiple doses ranging from 100 to 260 mg BID were evaluated to ascertain the optimal dosage. The MTD was not reached at the highest administered doses in either the single-dose (520 mg) or multiple-dose (260 mg BID) stages, and no DLTs were observed at any dose level. Pharmacokinetic analyses suggested dose-proportional exposure up to 200 mg BID, with no meaningful incremental gain at 260 mg BID.

The PARPi Landscape and Positioning of HWH340

PARPis have fundamentally transformed the treatment paradigm for cancers with HRR deficiencies. Currently, five PARPis—including olaparib, niraparib, rucaparib, talazoparib, and fuzuloparib—are approved across multiple indications, including ovarian, breast, pancreatic, and prostate cancers. While these agents share a common mechanism of catalytic PARP inhibition, they differ substantially in their PARP-trapping potency, pharmacokinetic properties, and toxicity profiles. Talazoparib,13 for instance, is distinguished by exceptionally potent PARP-trapping activity, which has been associated with enhanced preclinical anti-tumor efficacy but also more pronounced myelotoxicity. Conversely, olaparib exhibits weaker PARP-trapping and a comparatively more favorable hematological profile. The field is also witnessing a shift toward next-generation, more selective PARP1 inhibitors (eg, AZD5305,18 AZD9574)19 designed to preserve efficacy while minimizing hematological toxicity by sparing PARP2. However, the optimal balance between catalytic inhibition, trapping activity, and tolerability remains an area of active investigation.

HWH340 was designed as a PARP1/2 inhibitor with high selectivity, potent catalytic activity, and potent anti-tumor activity in BRCA-deficient xenograft models. Notably, HWH340 has not demonstrated PARP-trapping capacity, suggesting its mechanism of action is more closely aligned with olaparib than with talazoparib. This preclinical profile provided the fundamental scientific rationale for advancing HWH340 into clinical development, with the expectation of achieving meaningful anti-tumor activity while maintaining a manageable safety profile.

Safety and Tolerability

The safety findings from this Phase I study are largely consistent with the preclinical hypothesis. The AEs associated with HWH340 were predominantly mild to moderate in severity. The follow-up period for safety assessment was 28 ± 3 days after the last dose in the dose-expansion study. The most common severe AEs (grade ≥3; Table 5) were neutropenia, anemia, vomiting, leukopenia, thrombocytopenia, and elevated γ-glutamyltransferase levels—all of which are recognized class effects of PARPis. Notably, the incidence of hematological toxicities observed with HWH340 (anemia: 40.5% any grade, 14.3% grade ≥3; neutropenia: 40.5% any grade, 14.3% grade ≥3; thrombocytopenia: 23.8% any grade, 4.8% grade ≥3) fell within or below the ranges reported for marketed PARPis. The frequency of fatigue (16.7% any grade, 4.8% grade ≥3) was notably lower than the 50–70% reported for other agents in this class. Nausea (45.2%) and vomiting (33.3%) were the most common non-hematological AEs, with a higher incidence of grade ≥3 vomiting (11.9%) compared with the 1–8% typically reported for other PARPis.

It is noteworthy that three participants who died during the trial had experienced AEs. Two of these cases were adjudicated as unrelated to the study drug and were attributed to disease progression. However, one fatal case of paralytic intestinal obstruction in a patient with extensive abdominal metastases was assessed as possibly related to HWH340. This case underscores the potential for serious gastrointestinal toxicity associated with PARP inhibition—a class effect that, while uncommon, has been reported in the literature. Notably, this event occurred in the context of prolonged drug exposure and highlights the need for vigilant monitoring of gastrointestinal symptoms, particularly in patients with prior abdominal surgery, pre-existing bowel motility disorders, or concurrent medications that may affect gastrointestinal transit. PARPis have also been linked to cardiovascular AEs,20 including hypertension and thromboembolic events.20 QT interval prolongation was observed in four patients in this study (grades 1–3), warranting further investigation as a rare but clinically relevant AE for this class.

Dose Selection for Phase II

The RP2D was determined as 200 mg BID, based on an integrated assessment of PK exposure, safety profile, and preliminary anti-tumor activity. Although the highest tested dose of 260 mg BID did not reach the MTD, it was not selected as the RP2D. Steady-state PK analysis (Day 28) revealed that dose escalation from 200 mg to 260 mg BID did not yield a proportional increase in systemic exposure (AUC0–∞: 23,850.8 vs 23,262.0 ng·h/mL; Racc declined from 3.312 to 2.654), indicating no meaningful PK advantage at the higher dose. The AE profile further supported this decision: while 200 mg demonstrated superior preliminary anti-tumor activity over 140 mg (ORR: 31.8% vs 5.0%; median PFS: 4.07 vs 2.43 months), escalation to 260 mg was associated with higher incidences of certain toxicities (eg, anemia: 50% at 200 mg vs 100% at 260 mg; QT prolongation: 25% at 200 mg vs 75% at 260 mg) without additional preliminary anti-tumor activity benefit. Collectively, these data support 200 mg BID as the dose that best optimizes the benefit-risk balance for subsequent Phase II development.

Preliminary Anti-Tumor Activity and Its Interpretation

The observed anti-tumor activity, particularly the ORR of 31.8% and median PFS of 4.07 months at 200 mg BID, is encouraging and consistent with the preclinical rationale. However, these findings must be interpreted with caution. The dose-expansion cohorts were small (n=22 for the 200 mg group), the study was single-arm and open-label, and the patient population was heterogeneous with respect to tumor type, prior lines of therapy, and HRR/BRCA status. The subgroup comparisons, while biologically informative, were not pre-specified and lack the statistical power to support definitive conclusions. These preliminary anti-tumor effects are therefore best viewed as hypothesis-generating observations that require confirmation in larger, randomized, and adequately powered studies with biomarker-stratified patient selection.

Study Limitations

Several limitations of this study warrant consideration. First, the sample size was small, particularly in the dose-escalation phase, which is inherent to the Phase I nature of the trial but limits the generalizability of the findings. Second, the single-arm, open-label design precludes direct attribution of anti-tumor activity to HWH340 and introduces potential selection bias. Third, the DLT observation window in the single-dose phase was set at 7 days—a duration that, given the known gradual onset of certain hematological toxicities associated with PARPi, may not have fully captured all dose-limiting events. The 28-day observation window in the continuous-dosing phase was therefore considered more appropriate for toxicity assessment, consistent with the extended DLT evaluation windows adopted in other PARPi trials. Fourth, the PK analysis was limited by small cohort sizes and high inter-individual variability at certain dose levels, affecting the precision of exposure estimates. Fifth, the absence of pharmacodynamic data, such as PARP activity inhibition in peripheral blood mononuclear cells or tumor tissue, represents a missed opportunity to confirm target engagement and establish exposure–response relationships. Finally, the short follow-up duration (28 days post-treatment) precludes assessment of long-term risks, including myelodysplastic syndromes and secondary malignancies, which are known class effects requiring extended monitoring.

Collectively, the results of this first-in-human study demonstrate that HWH340 has a manageable safety profile, favorable PK characteristics, and encouraging preliminary anti-tumor activity at the 200 mg BID dose. The findings align with the preclinical expectation that catalytic PARP1/2 inhibition without potent PARP-trapping may offer a differentiated safety profile while preserving preliminary anti-tumor activity.

Conclusions

In this first-in-human Phase I study, HWH340 demonstrated a manageable safety profile, favorable pharmacokinetic characteristics, and preliminary anti-tumor activity in patients with advanced solid tumors harboring HRR-related gene mutations. Based on an integrated assessment of safety, steady-state PK exposure, and efficacy signals, 200 mg BID was selected as the RP2D, as it provided near-maximal systemic exposure comparable to that of the higher tested dose (260 mg BID) while offering a more favorable accumulation profile and better long-term tolerability. Notably, encouraging response rates were observed in patients with BRCA1/2 mutations (ORR 41.7% at 200 mg BID), and activity was also indicated in non-BRCA HRR-mutated subgroups, supporting further exploration of HWH340 in a broader HRR-deficient population.

However, given the exploratory nature of this Phase I study, several limitations must be acknowledged. The small sample sizes (particularly in subgroup analyses), single-arm open-label design, short DLT observation window in the single-dose phase, limited post-treatment follow-up (28 days), and absence of pharmacodynamic data collectively constrain the interpretability and generalizability of the findings. The observed efficacy data, while encouraging, are preliminary and should be viewed as hypothesis-generating rather than confirmatory.

These results provide a rationale for further clinical development of HWH340; however, the RP2D selection and its observed activity must be validated in larger, randomized, and adequately powered Phase II studies with longer follow-up, biomarker-stratified patient selection, integrated pharmacodynamic assessments, and robust statistical power to confirm target engagement and establish exposure–response relationships. The selected RP2D and its observed anti-tumor activity are currently being validated in an ongoing Phase II study (CTR20223238) to evaluate the safety and efficacy of HWH340 in patients with HRR-mutated tumors.

Abbreviations

AE(s), adverse event(s); AUC0-∞, area under the plasma concentration–time curve from zero to infinity; AUCss,12h, area under the plasma concentration–time curve at steady state from 0 to 12 h post-dose; BMI, body mass index; Cmax, maximum plasma concentration; CR, complete response; CV, coefficient of variation; DCR(s), disease control rate(s); DDS, dose determination dataset; DLT, dose-limiting toxicity; DOR, duration of response; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; FAS, full analysis set; HRD, homologous recombination deficiency; HRR, homologous recombination repair; MTD, maximum tolerated dose; ORR(s), objective response rate(s); OS, overall survival; PARPs, Poly ADP-ribose polymerases; PARPi(s), poly(ADP-ribose) polymerase inhibitor(s); PFS, progression-free survival; PPS, per-protocol set; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended phase 2 dose; SAE(s), serious adverse event(s); SD, stable disease; SS, safety set; TEAE(s), treatment-emergent AE(s); TGI, tumor growth inhibition; tmax, time to maximum plasma concentration; TMZ, temozolomide.

Data Sharing Statement

De-identified data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. The data that support the findings of this study are available from the corresponding author, Prof. Zhongsheng Tong, upon reasonable request.

Ethics Approval and Consent to Participate

This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and the local institutional review board at each participating site. The study was approved by the ethics committees of all sites. The ethics committee approval number of the leading site, Tianjin Medical University Cancer Institute and Hospital, is E2017225. All patients provided written consent prior to enrollment.

Consent for Publication

All patients gave written informed consent.

Acknowledgments

We thank all patients who participated in this study and the investigators and research staff at all centers. This multicenter study would not have been possible without the expertise and commitment of Dr. Xiaorong Dong from Union Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Drs. Shumei Wang and Jinsheng Shi from Cangzhou People’s Hospital, Dr. Lingzhi Zeng from Jiujiang First People’s Hospital, and Drs. Xueli Mo and Pingchao Xiang from Shougang Hospital, Peking University. We thank Suzhou HQ Pharmaceutical Technology Co., Ltd. for contributing to pharmacokinetic data analysis and Medjaden Inc. for scientific editing of this manuscript. An abstract of this study was presented at the ESMO conference in 2025.

This study was funded by the Tianjin Key Medical Discipline (Specialty) Construction Project, Clinical Trial Fund Project of Tianjin Medical University Cancer Hospital (358-2022-2), and Tianjin Medical University Cancer Hospital “14th Five-Year” Peak Discipline Support Program Project. This study was financially supported by Hubei Biomedical Industry and Technology Research Institute Co., Ltd.

Funding

This study was funded by the Tianjin Key Medical Discipline (Specialty) Construction Project, Clinical Trial Fund Project of Tianjin Medical University Cancer Hospital (358-2022-2), and Tianjin Medical University Cancer Hospital “14th Five-Year” Peak Discipline Support Program Project. This study was financially supported by Hubei Biomedical Industry and Technology Research Institute Co., Ltd.

Disclosure

Sheng Chen, Jingqiao Xu, and Wei Zhou were employees of Hubei Biomedical Industry and Technology Research Institute Co., Ltd. All authors declare no personal fees (lectures, presentations, speakers’ bureaus, manuscript writing, or educational events) from Hubei Biomedical Industry and Technology Research Institute Co., Ltd. during the conduct of the study. The authors report no other conflicts of interest in this work.

References

1. Sandhu SK, Yap TA, de Bono JS. The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment. Curr Drug Targets. 2011;12(14):2034–17. doi:10.2174/138945011798829438

2. Lin KY, Kraus WL. PARP inhibitors for cancer therapy. Cell. 2017;169(2):183. doi:10.1016/j.cell.2017.03.034

3. LYNPARZA® (olaparib). US food and drug administration website. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf. Accessed December20, 2019.

4. ZEJULATM (niraparib) capsules. US food and drug administration website. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. Accessed December20, 2019.

5. RUBRACA® (rucaparib) Tablets. US food and drug administration website. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf. Accessed December20, 2019.

6. TALZENNA™ (talazoparib) Capsules. US food and drug administration website. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf. Accessed January4, 2020.

7. Colombo N, Moore K, Scambia G, et al. Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Gynecol Oncol. 2021;163(1):41–49. doi:10.1016/j.ygyno.2021.07.016

8. Friedlander M, Gebski V, Gibbs E, et al. Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, Phase 3 randomised trial. Lancet Oncol. 2018;19(8):1126–1134. doi:10.1016/S1470-2045(18)30343-7

9. Frenel JS, Kim JW, Aryal N, et al. Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial. Ann Oncol. 2022;33(10):1021–1028. doi:10.1016/j.annonc.2022.06.011

10. Lee JY, Lee YY, Park JY, et al. Major clinical research advances in gynecologic cancer in 2022: highlight on late-line PARP inhibitor withdrawal in ovarian cancer, the impact of ARIEL-4, and SOLO-3. J Gynecol Oncol. 2023;34(2):e51. doi:10.3802/jgo.2023.34.e51

11. Shen Y, Aoyagi-Scharber M, Wang B. Trapping Poly(ADP-Ribose) polymerase. J Pharmacol Exp Ther. 2015;353(3):446–457. doi:10.1124/jpet.114.222448

12. Murai J, Huang S-YN, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13(2):433–443. doi:10.1158/1535-7163.MCT-13-0803

13. Guo C, Yu Y, Chakrabarti J, et al. Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment. Br J Clin Pharmacol. 2022;88(7):3392–3403. doi:10.1111/bcp.15294

14. Durairaj C, Chakrabarti J, Ferrario C, et al. The effect of renal impairment on the pharmacokinetics and safety of talazoparib in patients with advanced solid tumors. Clin Pharmacokinet. 2021;60(7):921–930. doi:10.1007/s40262-020-00983-y

15. Rolfo C, de Vos-Geelen J, Isambert N, et al. Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and renal impairment. Clin Pharmacokinet. 2019;58(9):1165–1174. doi:10.1007/s40262-019-00754-4

16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. doi:10.1016/j.ejca.2008.10.026

17. National Cancer Institute. 2010. Common terminology criteria for adverse events (CTCAE) v4.03 Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed August15, 2026.

18. Herencia-Ropero A, Llop-Guevara A, Staniszewska AD, et al. The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models. Genome Med. 2024;16(1):107. doi:10.1186/s13073-024-01370-z

19. Staniszewska AD, Pilger D, Gill SJ, et al. Preclinical characterization of AZD9574, a Blood–brain barrier penetrant inhibitor of PARP1. Clin Cancer Res. 2024;30(7):1338–1351. doi:10.1158/1078-0432.CCR-23-2094

20. Madariaga A, Bowering V, Ahrari S, Oza AM, Lheureux S. Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events. Int J Gynecol Cancer. 2020;30(7):903–915. doi:10.1136/ijgc-2020-001288