The first-in-human, first-in-class trial of the next-generation PARP (poly [ADP-ribose] polymerase) 1–selective inhibitor AZD5305 suggests this drug may be a welcome advance over its U.S. Food and Drug Administration (FDA)-approved predecessors in the treatment of solid tumors with alterations in homologous repair deficiency (HRD), improving pharmacokinetics, pharmacodynamics, and preliminary efficacy while reducing toxicity, according to a study presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.1
Timothy A. Yap, MBBS, PhD, FRCP
The phase I/II PETRA trial in patients whose tumors harbored HRD genetic alterations showed “robust target engagement” of PARP1, according to lead author Timothy A. Yap, MBBS, PhD, FRCP, who practices at The University of Texas MD Anderson Cancer Center, Houston. “AZD5305 significantly improved pharmacokinetics and exposure to target compared with all approved first-generation PARP inhibitors. The safety of this drug was also highly favorable at all dose levels, and antitumor activity was observed across doses, tumor types, and molecular subtypes—and was independent of prior PARP inhibitor use,” he stated.
Invited discussant of this study, Patricia LoRusso, DO, PhD, of Yale University Hospital Cancer Center, New Haven, Connecticut, used the word “amazing” in her review of this presentation: “The pharmacokinetics and pharmacodynamics are impressive. The drug appears extremely safe. This is an amazing drug, with very wide therapeutic index and little toxicity,” she told listeners.
Patricia LoRusso, DO, PhD
“PARP inhibitors target the DNA damage response,” Dr. Yap explained. There are four first-generation PARP inhibitors approved in multiple cancer indications globally, and all of them inhibit both PARP1 and PARP2. Hematologic toxicity is a class effect in first-generation PARP inhibitors. This is likely to be linked to the inhibition of PARP2, which is essential for erythropoiesis.”
“The hypothesis therefore is that a drug that potently and selectively targets PARP1 will reduce toxicity, improve pharmacokinetics and exposure to target, and potentially improve efficacy, as well as enable broader combination options,” Dr. Yap continued.
AZD5305 was designed as a highly potent and selective inhibitor of PARP1 with DNA-trapping activity. It does not bind to any other members of the PARP family and is selective against other oncology targets. AZD5305 is orally bioavailable. Preliminary studies showed it inhibits cancer growth in cell lines with HRD alterations, with no inhibitory effects in normal cells.
The global phase I/II PETRA trial evaluated AZD5305 as monotherapy in 61 patients with advanced metastatic breast, pancreatic, or prostate cancer with germline BRCA1, BRCA2, PALB2, or RAD51C loss-of-function mutations. Patients were allowed to receive up to one prior line of PARP inhibitor therapy. At study entry, patients had an Eastern Cooperative Oncology Performance of up to 2 and had to have a hemoglobin value of at least 9 g/dL, which are less stringent eligibility criteria compared with the first-generation PARP inhibitor trials.
The first patient enrolled in PETRA was dosed in November 2020, and the dose-escalation phase is ongoing. Patients were treated with oral AZD5305 once daily at several dose levels, from 6 mg/d to 140 mg/d.
About one-third of patients had ovarian cancer, and of these patients, 73% had platinum-resistant/refractory disease. About 30% had breast cancer, and most had BRCA2-mutated disease. Approximately 16% each had prostate or pancreatic cancer. Patients received a median of three lines of prior therapy; 72% had received a prior PARP inhibitor and/or platinum chemotherapy, and 41% had received both.
Safety Profile and Activity
Multiple dose levels were explored. Target concentration was achieved at the first dose level of 10 mg/d, and the highest dose level tested to date was 140 mg/d.
“This was much higher coverage over the target effective concentration than was achieved with all FDA-approved first-generation PARP inhibitors. The drug was well tolerated, with no treatment discontinuations. Only two patients had dose reductions, and at data cutoff, there were no dose-limiting toxicities or treatment discontinuations due to treatment-related adverse events,” Dr. Yap said.
The most common treatment-related adverse events were nausea, which was reported to be effectively managed with supportive measures and generally resolved after the first cycle, and anemia. “The emerging side-effect profile looks highly favorable,” Dr. Yap noted. The frequency of nausea or vomiting was much lower than with first-generation PARP inhibitors.
Of enrolled patients, 46 had measurable disease, and 6 were not evaluable by Response Evaluation Criteria in Solid Tumors. Of 40 patients, 10 had partial responses, and 11 had stable disease.
Responses were observed at all dose levels, across all tumor types, across mutation types, and in PARP inhibitor–naive and –experienced patients. A total of 19 patients remained on treatment over 16 weeks. There was preliminary evidence of early circulating tumor DNA responses and association with clinical response in five patients with BRCA2-mutated prostate cancer.
Studies of expansion cohorts in PARP inhibitor–naive patients are ongoing. Rational combinations, including with fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan, are being explored.
Expert Point of View
Invited discussant of the PETRA trial, Dr. LoRusso commented on the number of pluses for AZD5305. “In this phase I trial, we see differences from other PARP [poly (ADP-ribose) polymerase] inhibitors. The drug has significant selective PARP1 trapping over PARP2. There is a greater than 500-fold difference in PARylation [protein poly ADP-ribosylation], and it is more efficacious than first-generation PARP inhibitors. Compared with first-generation drugs, there were no alterations in erythroid precursors.”
Dr. LoRusso continued: “The study was focused on patients with HRD [homologous recombination deficiency] mutations alone. Regardless of dose or prior exposure to PARP inhibitor, we see efficacy. However, there were few, if any, complete responses.”
An unanswered question is whether combination strategies will improve the depth of response. “These results are impressive in patients with advanced disease. We need to explore whether AZD5305 can be used in the neoadjuvant and adjuvant settings and, even more important, as a potential preventive agent in high-risk patients. It might be good for women who may want to have children and may potentially delay oophorectomy. The phenomenal dosing flexibility lends itself to combinations with other agents to prevent toxicity, according to preclinical models,” Dr. LoRusso explained.
Dr. LoRusso continued: “We need to step back and identify the optimal phase II dose to move forward. It may be possible to advance many doses.”
“AZD5305 represents a major advance over first-generation PARP inhibitors,” she concluded. “The safety, pharmacokinetics, and pharmacodynamic profiles enhance utility and offer potential strategies toward intervention.”
DISCLOSURE: The study was funded by AstraZeneca. Dr. Yap has received institutional research support from Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace, and Zenith; has served as a consultant to AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Intellisphere, Janssen, Kyn, MEI Pharma, Mereo, Merck, Natera, Nexys, Novocure, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theranostics, Varian, Versant, Vibliome, Xinthera, ZaiLabs, and ZielBio; and has held stock in Seagen. Dr. LoRusso reported no conflicts of interest.
1. Yap TA, Im SA, Schram AM, et al: PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients with BRCA1/2, PALB2, or RAD51C/D mutations. AACR Annual Meeting 2022. Abstract CT007. Presented April 10, 2022.