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TheraP: [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer

In men whose prostate cancer had grown after chemotherapy, a radioactive drug that homes in on prostate cancer cells (lutetium-177 PSMA-617) shrank the PSA marker in more men, and caused fewer serious side effects, than the standard chemotherapy drug it was compared with.

TheraP (ANZUP 1603) was an open-label, randomised phase 2 trial at 11 Australian centres. Men with metastatic castration-resistant prostate cancer progressing after docetaxel, selected by centrally reviewed 68Ga-PSMA-11 and FDG PET/CT (excluding FDG-positive/PSMA-negative discordant disease), were randomised 1:1 to [177Lu]Lu-PSMA-617 (6.0-8.5 GBq IV every 6 weeks, up to six cycles) or cabazitaxel (20 mg/m2 IV every 3 weeks, up to ten cycles). The primary endpoint was a PSA50 response.

Of 291 men screened, 200 were PET-eligible and randomised. PSA50 responses were 66% with 177Lu-PSMA-617 versus 37% with cabazitaxel by intention to treat (difference 29 percentage points, 95% CI 16-42, p<0.0001). Grade 3-4 adverse events were less frequent with the radioligand (33% versus 53%). A mature follow-up analysis (Hofman et al., Lancet Oncology 2024) found overall survival was similar between arms (restricted mean survival time 19.1 versus 19.6 months), with substantial crossover (32% of the radioligand-therapy group and 20% of the cabazitaxel group went on to the other treatment).

TheraP was the first randomised trial to compare a PSMA radioligand head-to-head against a standard chemotherapy and used PET-based patient selection prospectively, a design later echoed by VISION and PSMAfore. It helped establish 177Lu-PSMA-617 (subsequently approved as Pluvicto) as a credible alternative to cabazitaxel in the post-docetaxel setting.

Randomised controlled trialChanged practice200 participants878 citations

Authors

Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, et al.

Published

Lancet, 2021

Full text

doi:10.1016/S0140-6736(21)00237-3 PubMed 33581798

Findings

PSA50 response: 66% (177Lu-PSMA-617) vs 37% (cabazitaxel) by intention to treat; difference 29% (95% CI 16-42), p<0.0001.
Grade 3-4 adverse events: 33% (98 men, PSMA arm) vs 53% (85 men, cabazitaxel arm); no deaths attributed to 177Lu-PSMA-617.
Mature follow-up (median 35.7 months): overall survival restricted mean survival time 19.1 months (PSMA) vs 19.6 months (cabazitaxel), difference -0.5 months (95% CI -3.7 to 2.7), p=0.77 - no evidence of an OS difference.
80 of 291 registered men (27%) were excluded after PET screening for low PSMA expression or FDG-discordant disease; their median survival was substantially shorter (RMST 11.0 months).

What it means

For men whose prostate cancer has grown after chemotherapy, a PSMA-targeted radioactive treatment worked at least as well as, and was gentler than, the chemotherapy drug it replaced - provided a PET scan first confirms the cancer takes up the PSMA tracer.

Caveats

Phase 2, single-country (Australia), open-label, not powered for overall survival as a primary endpoint.
High crossover between arms after the randomised period complicates the survival comparison.
PET-based selection excluded over a quarter of screened men, whose prognosis was worse regardless of treatment - the trial says nothing about that PSMA-negative group.