PARP1-Selective Inhibitors Generate Excitement in Solid Tumors

PARP1-selective inhibitors could represent the next frontier and generation of PARP inhibitors in oncology, potentially reducing the hematologic toxicity demonstrated in both preclinical and clinical research with first-generation dual inhibitors of PARP1 and PARP2.^1,2

“PARP is an enzyme that repairs single-strand breaks on DNA; this is one of the first defense mechanisms that allows cells to repair DNA and survive,” Neeraj Agarwal, MD, FASCO, said in an interview with OncologyLive. “If an [individual has] deficient…BRCA1 or BRCA2 or has a germline mutation, they are not able to repair a double-strand break in the [DNA of] their tumor.”

Agarwal added that inhibiting PARP causes the accumulation of single-strand DNA breaks, which eventually become double-strand breaks during cell division, noting that without the homologous recombination repair (HRR) mechanism intact, the cells will die (Figure).³ Agarwal is the Presidential Endowed Chair of Cancer Research, director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics, and professor of medicine at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

Presently, there are 4 FDA-approved PARP inhibitors in ovarian, breast, prostate, and pancreatic cancer. Three PARP inhibitors are approved in the maintenance setting in ovarian cancer: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca). Olaparib is also approved in breast cancer, as is talazoparib (Talzenna). Olaparib and rucaparib are also approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC), and olaparib is FDA approved in the maintenance setting in pancreatic cancer.^4-7

“All PARP inhibitors as a class can cause anemia, thrombocytopenia, and neutropenia; they’re considered [to be like] an oral form of chemotherapy because of their marrow suppression,” Andrew J. Armstrong, MD, MSc, professor of medicine in the Department of Medical Oncology, professor of pharmacology and cancer biology in the Department of Pharmacology & Cancer Biology, and professor of urology at Duke Cancer Center in Durham, North Carolina, said in an interview with OncologyLive. “There are concerns about any drug that is DNA damaging, potentially causing bone marrow toxicity and myelodysplastic syndrome. That’s something we’re looking out for, particularly as we move these drugs into earlier settings where patients have longer life expectancy.”

Saruparib Leads the Way for the Next Generation of PARP Inhibitors

Saruparib (formerly AZD5305) is a first-in-class, next-generation PARP inhibitor that selectively inhibits PARP1. Investigators hypothesized that inhibition of PARP1 alone could maintain and potentially improve the therapeutic benefit seen with PARP1/2 inhibitors with a lessened potential for hematologic and other toxicities. In findings from preclinical study, saruparib demonstrated a high level of potent selectivity for PARP1 and limited drug-drug interactions.⁷

“All the approved first-generation PARP inhibitors are dual PARP1/2 inhibitors,” Timothy A. Yap, MBBS, PhD, FRCP, said in an interview with OncologyLive. “However, only PARP1 trapping is required for synthetic lethality in homologous recombination deficiency settings. Therefore, the rationale is that saruparib could be developed through rational design to be highly selective for PARP1 with increased potency and improved physiochemical properties vs all the first-generation [FDA]-approved PARP inhibitors.” Yap is vice president and head of clinical development in the Therapeutics Discovery Division, and professor in the Department for Investigational Cancer Therapeutics (Phase I Program) in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Saruparib is being evaluated in patients with advanced/metastatic solid tumors, including HER2-negative breast, ovarian, pancreatic, and prostate cancer, in the ongoing phase 1/2 PETRA trial (NCT04644068). The open-label, multicenter study is evaluating saruparib monotherapy in adult patients with advanced solid malignant tumors harboring BRCA1/2, PALB2, RAD51C, or RAD51D mutations. The study also contains combination arms examining the agent in combination with paclitaxel, carboplatin with or without paclitaxel, fam-trastuzumab deruxtecan-nxki (Enhertu), datopotamab deruxtecan, and camizestrant.^8,9

The primary end point is safety and tolerability. Secondary end points include objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to response.⁹

During the American Association for Cancer Research Annual Meeting 2024 in San Diego, California, Yap presented preliminary findings from patients with molecularly selected ovarian, pancreatic, prostate, and HER2-negative breast cancer treated in the dose escalation portion (part A) and patients with HER2-negative breast cancer treated in the dose expansion portion (part B) of PETRA. Patients who received saruparib in part B (n = 31) achieved an ORR of 48.4% (95% CI, 35.7%-61.3%), a median DOR of 7.3 months (95% CI, 5.6-7.6), and a median PFS of 9.1 months (95% CI, 5.7-9.3).⁸

Patients treated at the 60-mg daily dose level in parts A and B (n = 141) experienced infrequent dose reductions (14.2%) and dose discontinuations (3.5%). The rates of grade 3 or higher anemia (11.3%), neutropenia (10.6%), and thrombocytopenia (5.7%) at this dose level in this group were all below 15%. The recommended phase 2 dose (RP2D) of saruparib was determined to be 60 mg once daily.

“Saruparib demonstrated a very favorable safety and tolerability profile, with no unexpected safety findings,” Yap said. “The adverse effects [AEs] were mainly grade 1 to 2, and AEs leading to dose reductions or discontinuations were highly infrequent. Importantly, the saruparib pharmacokinetics were linear, and it was able to achieve much higher target pharmacokinetic coverage vs all the approved PARP inhibitors.”

Investigators are also examining saruparib as a combination component in multiple clinical trials. Building on the positive results reported in PETRA, investigators have initiated the phase 3 EvoPAR-Prostate01 trial (NCT06120491), the trial design of which was presented during the 2024 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹⁰

EvoPAR-Prostate01 is a double-blind, placebo-controlled, multicenter global trial that is enrolling adult patients with metastatic castration-sensitive prostate cancer (CSPC) that is either de novo or recurrent. Patients must also have low- or high-volume disease with an ECOG performance status of 1 or less. Patients must also be receiving androgen deprivation therapy in combination with a gonadotropin-releasing hormone analogue through the duration of the trial or have undergone bilateral orchiectomy and be suitable for treatment with next-generation hormonal agents.

The study includes 2 cohorts, with 1 encompassing patients with HRR mutations and 1 containing patients without. In the cohort with HRR mutations, which will enroll approximately 550 patients, patients must have mutations in at least 1 of the following genes: BRCA1/2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, and/or BARD1. The cohort without HRR mutations will enroll approximately 1250 patients.

The primary end point is radiographic PFS per RECIST v1.1 criteria and/or Prostate Cancer Working Group 3 criteria in patients with BRCA- and HRR-mutated disease as well as in those with no HRR mutations. Overall survival is a key secondary end point; other secondary end points include time to second progression, health-related quality of life, pharmacokinetics, and safety and tolerability.

In both cohorts, patients will be randomly assigned 1:1 to receive saruparib at the RP2D in combination with physician’s choice of a next-generation hormonal agent or placebo plus a next-generation hormonal agent. Hormonal agents available for selection in the study consist of abiraterone acetate (Zytiga), darolutamide (Nubeqa), or enzalutamide (Xtandi). Enrollment in EvoPAR-Prostate01 began in November 2023 and is ongoing. “The hope is that by having a wide therapeutic index but at the same time achieving much higher pharmacokinetic drug exposures, we’ll be able to combine saruparib more optimally with other drugs,” Yap explained.

Beyond EvoPAR-Prostate01, saruparib is also being investigated in combination with androgen receptor (AR) pathway inhibitors in patients with either metastatic CRPC or CSPC in the phase 1/2 PETRANHA study (NCT05367440). PETRANHA is enrolling adult patients irrespective of HRR mutation status; patients must also have an ECOG performance status of 1 or less. The primary end point is safety and tolerability; secondary end points include pharmacokinetics and preliminary antitumor activity.¹¹

Patients in arm A (n = 11) received daily oral enzalutamide at a dose of 160 mg, those in arm B (n = 19) received daily oral abiraterone at a dose of 1000 mg plus prednisone at a dose of 5 mg, and those in arm C (n = 18) received darolutamide at a dose of 600 mg twice daily. All patients were also treated with saruparib at the RP2D.

Interim safety findings from PETRANHA, presented during the 2024 Genitourinary Cancers Symposium in San Francisco, California, demonstrated that at the data cutoff of July 10, 2023, patients with metastatic CRPC (n = 32) and metastatic CSPC (n = 16) experienced serious AEs at rates of 25% and 6.3%, respectively, with 3.1% and 6.3% of these being related to treatment, respectively. Patients in both arms experienced grade 3 or higher treatment-emergent AEs (28.1% vs 31.3%) and grade 3 or higher treatment-related AEs (15.6% vs 31.3%). No dose-limiting toxicities or deaths due to AEs were reported, although 1 patient in each group was forced to discontinue treatment with saruparib due to an AE.

Notably, no significant drug-drug interactions were reported with any of the combinations. Study authors concluded that the initial data from PETRANHA showed that saruparib can be safely combined with enzalutamide, abiraterone, or darolutamide.

“There’s interest in expanding the PARP-AR combination successes into other settings, [such as] nonmetastatic CRPC and even nonmetastatic high-risk hormone-sensitive prostate cancer,” Armstrong said. “There’s a lot of discussion and ongoing study design around earlier disease settings—even neoadjuvant studies that are being explored to eradicate prostate cancer before it spreads.”

References

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2. LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol. 2019;20(1):e15-e28. doi:10.1016/S1470-2045(18)30786-1
3. Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. Target Oncol. 2021;16(3):255-282. doi:10.1007/s11523-021-00796-4
4. Smith AJB, Apple A, Hugo A, Haggerty A, Ko EM. Prior authorization for FDA-approved PARP inhibitors in ovarian cancer. Gynecol Oncol Rep. 2024;52:101335. doi:10.1016/j.gore.2024.101335
5. Daly GR, AlRawashdeh MM, McGrath J, et al. PARP inhibitors in breast cancer: a short communication. Curr Oncol Rep. 2024;26(2):103-113. doi:10.1007/s11912-023-01488-0
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7. FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. FDA. December 30, 2019. Accessed August 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma
8. Yap TA, Schram AM, Balmaña J, et al. PETRA: first-in-human phase 1/2a trial of the first-in-class new generation poly(ADP-ribose) polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations. Abstract presented at: American Association for Cancer Research Annual Meeting 2024; April 5-10, 2024; San Diego, CA. Abstract CT014.
9. Study of AZD5305 as monotherapy and in combination with anti-cancer agents in patients with advanced solid malignancies (PETRA). ClinicalTrials.gov. Updated June 25, 2024. Accessed August 16, 2024. https://clinicaltrials.gov/study/NCT04644068
10. Chi KN, Agarwal N, Armstrong AJ, et al. Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01). J Clin Oncol. 2024;42(suppl 16):TPS5123. doi:10.1200/JCO.2024.42.16_suppl.TPS5123
11. Azad A, Voskoboynik M, Joshua AM, et al. PETRANHA: phase 1/2 study of AZD5305 + novel hormonal agents in patients with metastatic prostate cancer–interim safety and pharmacokinetic results. J Clin Oncol. 2024;42(suppl 4):123. doi:10.1200/JCO.2024.42.4_suppl.123