Combo of 177Lu-PSMA-617 and novel radiosensitizer shows promise

Preclinical data have provided further evidence that adding the novel radiosensitizer idronoxil (NOX66; Veyonda) to ¹⁷⁷Lu-PSMA-617 may improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC), according to Noxopharm, the manufacturer of idronoxil.¹

Previously reported data from the phase 1/2 LUPIN trial² showed that the combination induced a median overall survival (OS) of 19.7 months in patients with mCRPC and no other treatment alternatives; however, the additive benefit of idronoxil was unknown.

“The LUPIN study was a nonrandomized study, so the question remained of how much the remarkable outcome of 19.7 months was due to the combination effect versus [¹⁷⁷Lu-PSMA-617] monotherapy alone,” Graham Kelly, PhD, CEO of Noxopharm, stated in a press release. “The preclinical study results confirmed that [¹⁷⁷Lu-PSMA-617] monotherapy had an impressive anticancer effect on tumor growth—but when Veyonda was added, the tumors mostly disappeared.”

The preclinical study examined the combination in mice bearing human prostate cancer xenografts. Commenting on the preclinical trial, lead study author Kristofer Thurecht, PhD, The University of Queensland, stated in the press release, “The combination of Veyonda with [¹⁷⁷Lu-PSMA-617] exhibited an impressive synergistic therapeutic response, with sustained and almost complete regression of the tumor and minimally observed systemic toxicity. This combined response was not observed in any of the animals treated with monotherapy.”

LUPIN trial

The phase 1/2 LUPIN trial included 56 men with mCRPC and progressive disease who had prior taxane and androgen signaling inhibitor treatment. All men had prior docetaxel and 95% (n = 53) had prior cabazitaxel (Jevtana).

Treatment consisted of up to 6 doses of ¹⁷⁷Lutetium-PSMA-617 on day 1 in combination with idronoxil suppository on days 1 to 10 of 6-week cycles. All but 2 patients received ≥2 cycles of the combination, and nearly half (46%) completed 6 cycles.

Overall, 86% of patients had at least some reduction in PSA and 61% had a ≥50% PSA reduction. The median PSA progression-free survival and median OS were 7.5 and 19.7 months, respectively. The most frequently reported adverse events included anemia, fatigue, and xerostomia. Thirty-eight percent of patients experienced anal irritation resulted from idronoxil.

“NOX66 with ¹⁷⁷Lu-PSMA-617 is a safe and feasible therapeutic strategy in men treated third-line and beyond for mCRPC. PSMA SUVmean, PSMA avid tumor volume, and duration of treatment with ASI were independently associated with outcome,” the authors wrote in their study conclusion.

Results from the phase 3 VISION trial reported earlier this year at the 2021 ASCO Annual Meeting showed that adding ¹⁷⁷Lu-PSMA-617 to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone in patients with progressive, PSMA-positive mCRPC.³ Adding ¹⁷⁷Lu-PSMA-617 to SOC also led to a 60% reduction in the risk of disease progression or death.

References

1. Noxopharm Pre-clinical Study Confirms Survival Advantage of Combination LuPSMA Therapy in Prostate Cancer. Published online August 12, 2021. Accessed August 16, 2021. https://bwnews.pr/3g8ESFI.

2. Pathmanandavel S, Crumbaker M, Yam AO, et al. 177Lutetium PSMA-617 and idronoxil (NOX66) in men with end-stage metastatic castrate-resistant prostate cancer (LuPIN): Patient outcomes and predictors of treatment response of a phase I/II trial [published online ahead of print July 29, 2021]. J Nucl Med. doi: 10.2967/jnumed.121.262552.

3. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4).