LuPSMA and enzalutamide: a promising combination

The combination of enzalutamide and lutetium-177-PSMA-617 (LuPSMA) enhanced anticancer effects in prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) participants, the first results of the ENZA-p trial showed.

Both the nonsteroidal antiandrogen enzalutamide and PSMA-specific radionucleotide treatment LuPSMA improve overall survival (OS) in mCRPC [1,2]. It is also known that treatment with enzalutamide upregulates PSMA expression in tumour cells. Therefore, combining enzalutamide and LuPSMA could be synergistic. This hypothesis was tested in the randomised phase 2 ENZA-p trial (NCT04419402). The results from the first interim analysis at a median follow-up of 20 months were presented by Prof. Louise Emmet (St Vincent’s Hospital Sydney, Australia) [3].

A total of 162 participants with mCRPC, rising prostate-specific antigen (PSA) levels, at least 2 high-risk factors for early enzalutamide failure, and a positive ⁶⁸Ga-PSMA scan were randomised 1:1 to enzalutamide or enzalutamide plus LuPSMA. LuPSMA was given 15 days after the start of enzalutamide and again 6 weeks later. Participants in the LuPSMA arm who had maintained a positive PSMA scan at day 92 were offered 2 extra LuPSMA doses. The primary endpoint is PSA-progression-free survival (PSA-PFS). The secondary endpoints include radiological PFS (rPFS), PSA50% and PSA90% response rates (PSA50RR, PSA90RR), adverse events, and OS.

LuPSMA favoured PSA-PFS as the primary endpoint. The median PSA-PFS was 13 months in the LuPSMA arm versus 7.8 months in the enzalutamide alone arm (HR 0.43; 95% CI 0.29–0.63; P<0.00001). The PSA response rates were also in favour of LuPSMA, where PSA50RR was 93% versus 67% in the LuPSMA and enzalutamide arms, respectively. PSA90RR was 78% versus 37%. Adverse events were similar in both arms.

“These results provide strong evidence that the combination of enzalutamide and LuPSMA has enhanced anticancer effects in PSMA-positive mCRPC patients,” Prof. Emmet concluded. “In addition, the adaptive LuPSMA dosing has the potential to reduce toxicity by only administering in patients with persistent PSMA-avid disease.” The progression-free and overall survival data are planned for July 2024.

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   1. Beer TM, et al. N Engl J Med 2014;371:424–433.
   2. Beer TM, et al. N Engl J Med 2014;371:424–433..
   3. Emmett L, et al Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901). Abstract LBA84, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December, 2023