TheraP study comparing radioligand treatment with ¹⁷⁷Lu-PSMA to the chemotherapy using cabazitaxel

April 27, 2022October 3, 2024anastasiaNews

TheraP, a phase II trial comparing radioligand treatment with ¹⁷⁷Lu-PSMA-617 to the chemotherapy using cabazitaxel was finalized with ¹⁷⁷Lu-PSMA demonstrating a clear advantage over the chemotherapy.

Probands’ selection criteria

200 men with mCRPC, overwhelmingly ADT-pretreated (91%), were selected based on ⁶⁸Ga-PSMA PET/CT and ¹⁸F-FDG PET/CT. ⁶⁸Ga-PSMA PET/CT was meant to detect the sufficiency of PSMA (min Standardized Uptake Value >20) in the tumor and metastases, a prerequisite for the radioligand therapy; otherwise, the radioligands have nowhere to dock to put it plainly. ¹⁸F-FDG PET/CT shows the glucose metabolism of the tumor and its metastases: high metabolism signals the aggressivity of cancer. Patients with lesions with discordant ⁶⁸Ga-PSMA PET/CT and ¹⁸F-FDG PET/CT pictures, meaning aggressive lesions with insufficient PSMA, were also excluded. After random assignment, 98 men were assigned to ¹⁷⁷Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles), and 85 – to cabazitaxel (20 mg/m² intravenously every 3 weeks for up to ten cycles).

Findings

The primary endpoint or the main success criterion was defined as PSA decline above 50% from the starting values. ¹⁷⁷Lu-PSMA-617 compared with cabazitaxel led to a higher PSA response and fewer grade 3 or 4 adverse events.

PSA decline of over 50% was more frequent among those treated with the ¹⁷⁷Lu-PSMA-617 than in the cabazitaxel group: 65 vs 37 PSA responses or 66% vs 44%. Moreover, the higher the SUV was, the better were the odds of the therapy being effective, even with more aggressive tumors (Metabolically active Tumor Volume > 200ml).

Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the ¹⁷⁷Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group.

¹⁷⁷Lu-PSMA-617 delayed progression as compared with cabazitaxel. Progression-free survival was defined as the interval from randomisation to first evidence of PSA progression defined by an increase of at least 25% and at least 2 ng/mL after 12 weeks.

Discussion

This study provides complementary data to the VISION trial because cabazitaxel was not included in the standard-of-care group in the VISION trial. Both trials used ⁶⁸Ga-PSMA-11 for patient selection, with TheraP using an additional quantitative PET parameter (uptake SUVmax) and ¹⁸F-FDG to identify patients with discordant ¹⁸F-FDG-positive, PSMA-negative lesions.

It should be noted that prostate cancer amongst the probands was really advanced – 85% had over 20 metastatic lesions. The efficacy and safety profile of ¹⁷⁷Lu-PSMA-617 demonstrated in all trials so far has generated interest in exploring the use of ¹⁷⁷Lu-PSMA earlier in the course of the disease. Multiple trials are underway including ¹⁷⁷Lu-PSMA combined with immune checkpoint inhibitors, a poly(ADPribose) polymerase inhibitor, or enzalutamide. Use of ¹⁷⁷Lu-PSMA up-front in men with newly diagnosed metastatic hormone-sensitive prostate cancer is also being explored.

The ability to select patients who are most likely to benefit from ¹⁷⁷Lu-PSMA therapy is a key advantage of the theranostic approach of combining imaging and therapy modalities.