Background: Combination PARPi plus WEE1i (PARPi + WEE1i) induces replication stress (RS), DNA damage, and abrogates the G2 cell cycle checkpoint. Concurrent PARPi + WEE1i administration effectively inhibits tumor growth but is poorly tolerated. Sequential PARPi+WEE1i administration in vivo mirrors concurrent dosing in cells with high basal RS, while normal cells with low basal RS are protected from DNA damage, improving tolerability while preserving efficacy (Fang et al., Cancer Cell 2019). Based on these compelling preclinical data, the NCI CTEP-sponsored STAR study investigated sequential ola+ada in pts with DDR aberrant advanced tumors (NCT04197713).
Materials and Methods: Pts with advanced cancer with actionable DDR variants were enrolled. Prior PARPi was allowed. Dose escalation followed Bayesian Optimal Interval Design; Dose Level (DL) 1: ola 300 mg BID days (D) 1–5, 15–19 + ada 250 mg QD D8–12, 22–26; DL 2: ola 300 mg BID D1– 5, 15–19 + ada 300 mg QD D8–12, 22–26; Q28 days. Primary objectives were safety and recommended phase 2 dose (RP2D). Secondary objectives were antitumor activity, PK, PD and biomarkers of response/resistance. Serial tumor and blood sampling were obtained for tumor whole exome and RNA sequencing, RAD51-IF, multiplex IHC and ctDNA NGS.
Results: 13 pts (M:F 2:11; ECOG PS 0:1: 4/9; mean age: 50y (35–72) with breast (n = 5), ovarian (n = 5), colorectal, gastric, prostate (n = 1) cancers were enrolled. Actionable genomic alterations included BRCA1/2 (n = 8), CCNE1 amplification (n = 3), ARID1A (n = 2), ATM (n = 1), PALB2 (n = 1). 10/13 pts had ≥3 lines of prior systemic therapy; 7/13 had progressed on prior PARPi. 3/13 pts were treated with sequential ola+ada at DL 1, 10/13 at DL 2. Common toxicities: grade (G) 1/2 nausea (10/13), anemia (7/13), fatigue (7/13), vomiting (7/13), and diarrhea (4/13). No DLTs occurred. Non-DLT ≥G3 myelosuppression occurred in 2/13 pts who were heavily pre-treated (≥5 prior lines). Dose reduction occurred in only 1/13 pts even with long term follow-up. 3/12 evaluable pts had RECIST1.1 PR and/or GCIG CA125 response, and 5/12 pts had SD ≥4 mths for 66.7% (8/12) disease control rate; 4 of these 8 pts had progressed on prior PARPi. RECIST1.1 PRs were seen in BRCA2m ER+ breast cancer pt (−57%,17 wks) and BRCA2m PARPi-resistant ovarian cancer pt (−50%; 26 wks) who had BRCA2m reversion at baseline. A CCNE1 amp ovarian cancer pt had GCIG CA125 response and SD 20 wks. Translational analyses are ongoing.
Conclusion: The novel sequential dosing schedule of ola + ada is well tolerated at full monotherapy dosing of each drug, with antitumor activity in pts with post-PARPi DDR aberrant tumors. RP2D was ola 300 mg BID D1–5, 15–19 + ada 300 mg OD D8–12, 22–26; Q28 days. Planned expansion cohorts include (1) pts with BRCA1/2 m tumors with intrinsic PARPi resistance and (2) pts with DDR mutated tumors with acquired PARPi resistance.
Conflict of interest:
Ownership: T.A.Y holds stocks in Seagen.
Advisory Board: T.A.Y has received fees for consulting from AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 The rapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio.
Board of Directors: N/A.
Corporate-sponsored Research: T.A.Y has received research support (paid to his institution) from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, Artios, 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.
Other Substantive Relationships: N/A.