LBA65 - Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH)

Background

Metastatic castration-resistant prostate cancer (mCRPC) is a fatal condition with a substantial unmet need. ¹⁷⁷Lu-PNT2002 is a beta-emitting radioisotope chelated to a small-molecule ligand targeting PSMA.

Methods

SPLASH is an open label phase 3 trial which enrolled PSMA PET-positive patients (pts) with mCRPC who progressed on one ARPI and have not received chemotherapy for castration resistant disease. Pts were randomized 2:1 to either ¹⁷⁷Lu-PNT2002 (6.8 GBq IV q8w up to 4 cycles) or alternate ARPI. The primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) using RECIST 1.1/PCWG3. Additional key endpoints included overall survival (OS), objective response rate (ORR), PSA50, HRQoL and safety. Crossover from alternate ARPI to ¹⁷⁷Lu-PNT2002 was allowed after disease progression confirmed by BICR.

Results

Of 488 pts screened with PSMA PET, 90.4% were PSMA positive; 412 were randomized to ¹⁷⁷Lu-PNT2002 (n=276, median 4 cycles) or alternate ARPI (n=136). Demographics and baseline characteristics were well balanced between ¹⁷⁷Lu-PNT2002 and ARPI: ECOG status 0: 58.7% vs. 55.9%; M0 status: 10.1% vs. 11.0%, respectively. Crossover rate was 84.6% (77/91). rPFS primary endpoint (mos, (95% CI)) was improved in pts receiving ¹⁷⁷Lu-PNT2002 (9.5, (7.4, 10.0)) compared to ARPI (6.0, (4.7, 7.9)) (HR (95% CI): 0.71 (0.55, 0.92), p=0.0088). Other efficacy outcomes are provided in the table. Incidence of TEAEs leading to treatment discontinuation and grade ≥3 TEAEs were both lower with ¹⁷⁷Lu-PNT2002 vs. ARPI ((5/269) 1.9% vs. (8/130) 6.2% and 30.1% vs. 36.9%, respectively). Most common TEAEs of ¹⁷⁷Lu-PNT2002 were fatigue (53.5%), dry mouth (37.2%) and nausea (31.2%). Table: LBA65

*assumes proportional hazards **exploratory OS crossover adjusted methods ***unconfirmed

Conclusions

¹⁷⁷Lu-PNT2002 was well tolerated and improved rPFS, ORR, PSA50 and HRQoL in patients with PSMA-positive mCRPC in the pre-chemotherapy setting compared to alternative ARPI.

Clinical trial identification

NCT04647526.

Editorial acknowledgement

Legal entity responsible for the study

Lantheus.

Funding

POINT/Lantheus.

Disclosure

O. Sartor: Financial Interests, Personal, Stocks or ownership: Clarity Pharmaceuticals, Fusion Pharmaceuticals, Lilly, J&J, Ratiopharm; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, AstraZeneca, Fusion Pharmaceuticals, Merck, Point Biopharma, Lantheus; Financial Interests, Institutional, Research Funding: Bayer, Janssen/J&J, Novartis, Point. D.M. Jiang: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Bayer, EMD Serono, Ipsen, Janssen Oncology; Financial Interests, Personal, Advisory Role: AstraZeneca/Merck, Bayer, Janssen Oncology, McKesson, EMD Serono, Pfizer, Novartis AAA; Financial Interests, Institutional, Research Funding: Amgen, Astellas Pharma; Financial Interests, Personal, Research Funding: Tersera; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: EMD Serono. M. Smoragiewicz: Financial Interests, Institutional, Research Funding: Point. M. Zibelman: Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Advisory Role: AVEO, Blue Earth Diagnostics, EMD Serono, Exelixis, Janssen, Merck, Pfizer; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Exelixis, Horizon Pharma; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Dava Oncology. A. Flechon: Financial Interests, Personal, Other, Honorarium and travel expenses: Janssen, Astellas, Novartis, Adacap, Bayer, Pfizer, AstraZeneca. G. El-Haddad: Financial Interests, Personal, Advisory Role: Bayer, Boston Scientific, Terumo; Financial Interests, Personal, Advisory Board: Northstar Medical radioisotopes. G. Abikhzer: Financial Interests, Personal, Speaker, Consultant, Advisor: Advanced Accelerator Applications. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Pfizer, Myovant, Novartis, AstraZeneca, Merck; Financial Interests, Institutional, Local PI: Novartis, Astellas, bayer, janssen, sanofi, bms, amgen, pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeenca. R. Tutrone: Financial Interests, Personal, Full or part-time Employment: Chesapeake Urology; Financial Interests, Personal, Stocks or ownership: Compass Therapeutics, GSK, Myovant Sciences, Novartis, Nymox, Veru; Financial Interests, Personal, Advisory Role: Exosome Diagnostics, Myovant Sciences, Novartis, Nymox; Financial Interests, Personal, Speaker’s Bureau: Exosome Diagnostics, Medivation/Astellas, Pfizer; Financial Interests, Institutional, Research Funding: Advantagene, Bayer, Dendreon, Exosome Diagnostics, Genomic Health, Janssen Oncology, MDxHealth, Medivation/Astellas, Merck, POINT Biopharma, Veru. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: Ambrx, Telix Pharma, Blue Earth Diagnostics, Point Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, EMD Serono, Regeneron, Daiichi Sankyo; Financial Interests, Personal, Other, DSMB: Boston Scientific; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, Point Biopharma, Clarity, Ambrx, Promontory, Telix. J. Calais: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, Bayer, Blue Earth Diagnostics, Curium Pharma, DS Pharma, Fibrogen, GE Healthcare, Isoray, IBA RadioPharma, Janssen, Lightpointmedical, Lantheus, Monrol, Novartis, Pfizer, Point Biopharma, Radiomedix, Sanofi, Siemens - Varian, Sofie, Telix Pharmaceuticals; Financial Interests, Institutional, Research Funding: Progenics, Point Biopharma, Novartis. A.R. Hansen: Financial Interests, Personal, Other, Honoraria: MSD, Bayer; Financial Interests, Personal, Advisory Role: MSD, Pfizer, Bayer; Financial Interests, Institutional, Research Funding: BMS, Pfizer, GSK, Eisai, Janssen, MSD, AstraZeneca, Roche, Boehringer Ingelheim, Genentech, Macrogenics. W. Wu, J. Jensen, C.R. Trieu, N. Fleshner: Financial Interests, Personal, Full or part-time Employment: Point Biopharma, a wholly owned subsidiary of Eli Lilly and Company. I. Teslenko: Financial Interests, Personal, Full or part-time Employment: Lantheus; Financial Interests, Personal, Stocks/Shares: Lantheus. J.G. Provost: Financial Interests, Personal, Full or part-time Employment: Lantheus. K.N. Chi: Financial Interests, Personal, Other, Honoraria: Astellas Pharma, AstraZeneca, BMS, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche; Financial Interests, Institutional, Research Funding: Astellas Pharma, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche. All other authors have declared no conflicts of interest.