5500 Background: LuPSMA is a radiolabeled small molecule that delivers therapeutic β-radiation to PSMA-expressing tumors. Encouraging efficacy and safety has been shown in non-randomized studies of mCRPC. TheraP is a randomized phase II trial comparing LuPSMA vs cabazitaxel in men with mCRPC progressing after docetaxel. Methods: Men with mCRPC, and imaging with 68Ga-PSMA-11 and 18F-FDG PET/CT that confirmed high PSMA-expression and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8GBq q6weeks up to 6 cycles) vs cabazitaxel (20mg/m2 q3weeks up to 10 cycles); stratified by disease burden (>20 vs ≤20 sites), prior novel antiandrogens (NAA; abiraterone or enzalutamide), and study site. The primary endpoint was PSA response rate (PSA50-RR) defined by ≥50% reduction. Secondary efficacy endpoints included PSA-progression-free survival (PSA-PFS) and overall survival (OS). Data cut-off was 31DEC19 at this first pre-specified analysis. Results: 200 (median age 72 y, prior NAA 91%, >20 lesions 78%) of 291 PET screened men were randomised to LuPSMA (N=99) or cabazitaxel (N=101). 17 patients withdrew or died before receiving study treatment (1 LuPSMA vs 16 cabazitaxel). The PSA50-RR was higher in those assigned LuPSMA than cabazitaxel (65/99 [66%; 95%CI 56-75] vs 37/101 [37%; 95%CI 27-46]; P<0.001). At a median follow-up of 11.3 months, LuPSMA significantly improved PSA-PFS (HR 0.63, 95%CI 0.45-0.88, P=0.007; 143 events with next pre-specified analysis planned after 170 events). Efficacy results were similar when analyses were restricted to per-protocol treated men. OS data remains immature (57 deaths). Grade III-IV adverse events (AEs) occurred in 31/98 (32%) LuPSMA-treated men vs 42/85 (49%) in cabazitaxel-treated men. Discontinuations for toxicity occurred in 1/98 (1%) LuPSMA vs 3/85 (4%) cabazitaxel-treated. There were no treatment-related deaths. Conclusions: In men with docetaxel-treated mCRPC, LuPSMA was more active (PSA50-RR) than cabazitaxel with relatively fewer G3-4 AEs and PSA-PFS favoring LuPSMA. Clinical trial information: NCT03392428 .

5000 Background: We previously reported that in men with mCRPC progressing after docetaxel randomly assigned LuPSMA vs. cabazitaxel (Lancet 2021), those assigned LuPSMA has significant improvements in PSA response rate (66% vs. 37%), RECIST response rate (49% vs. 24%), progression-free survival (HR 0.63), less G3-4 toxicities (33% vs. 53%) and better patient-reported outcomes. We now report the secondary endpoint of overall survival (OS) with mature follow-up, for trial participants, and also those initially excluded because of low PSMA-expression or discordant disease on imaging with PSMA-PET and FDG-PET. Methods: Eligibility for the TheraP trial required mCRPC progressing after docetaxel, PET imaging with 68Ga-PSMA-11 that showed high PSMA-expression (at least one site with SUVmax≥20), and 18F-FDG demonstrating no sites of disease of FDG-positive and PSMA-negative (discordant disease). Participants were randomly assigned treatment with LuPSMA (8.5-6GBq every 6 weeks, maximum 6 cycles) vs cabazitaxel (20mg/m2 every 3 weeks, maximum 10 cycles). OS was analyzed by intention-to-treat and summarized by restricted mean survival time (RMST) to account for non-proportional hazards. Results: 291 patients were screened from 6 Feb 2018 to 3 Sep 2019: 200 were eligible and randomly assigned LuPSMA (99) or cabazitaxel (101); 80 of 291 (27%) registered after initial eligibility were excluded after PSMA/FDG-PET(51 SUVmax < 20, 29 discordant), with follow-up available in 61 of the 80 (76%). After a median follow-up time of 36 months (data cut-off 31 Dec 2021), death was reported in 70/101 assigned cabazitaxel, 77/99 assigned LuPSMA, and 55/61 excluded after PSMA/FDG-PET. Subsequent treatments among those assigned cabazitaxel included cabazitaxel in 21, and LuPSMA in 20; and among those assigned LuPSMA included additional LuPSMA in 5, and cabazitaxel in 32. Overall survival was similar in those randomly assigned LuPSMA versus cabazitaxel (RMST to 36 months was 19.1 vs. 19.6 months, difference -0.5, 95% CI -3.7 to + 2.7). No additional safety signals were identified with longer follow-up. Among 61 men excluded by imaging with PSMA/FDG-PET before randomisation, RMST to 36 months was 11.0 months (95% CI 9.0 to 13.1), following treatment that included cabazitaxel in 29 (48%) and LuPSMA in 3 (5%). Conclusions: LuPSMA is a suitable option for men with mCRPC progressing after docetaxel, with lower adverse events, higher response rates, improved patient-reported outcomes, and similar OS compared with cabazitaxel. Median survival was considerably shorter for patients excluded on PSMA/FDG-PET due to either low PSMA expression or FDG-discordant disease who would otherwise be eligible for LuPSMA. Clinical trial information: NCT03392428.

10 Background: The TheraP trial showed that LuPSMA improved PSA≥50% response rate (PSA50-RR), PSA-PFS, and radiographic PFS (rPFS) compared with cabazitaxel in mCRPC progressing after docetaxel. Study inclusion required high PSMA uptake (SUVmax≥20) and no lesions that were FDG+ and PSMA-. Here we report on PSMA PET and FDG PET as potential predictive and prognostic biomarkers. Methods: We prospectively analysed semi-automated quantitative PET parameters in centrally- collected 68Ga-PSMA-11 PET and 18F-FDG PET in 200 eligible men. SUVmean ≥10 on PSMA PET was evaluated as a predictive biomarker for response to Lu-PSMA vs cabazitaxel. Metabolic tumor volume (MTV) ≥200mL on FDG PET was tested as a prognostic biomarker accounting for the randomly assigned treatment. Quantitative PET cut-offs were pre-specified from prior research (PMID:32140802). Responses were defined according to PSA50-RR (primary endpoint), PSA-PFS and rPFS. Binary and PFS endpoints were analyzed using logistic and Cox regression, respectively. Results: Very high PSMA uptake on PSMA PET (SUVmean≥10) was seen in 35/99 (35%) assigned LuPSMA and 30/101 (30%) assigned cabazitaxel. The odds of a response to LuPSMA vs. cabazitaxel were significantly higher for men with SUVmean≥10 (OR 12.2, 95%CI 3.4-59 vs. 2.2, 95%CI 1.1-4.5; p = 0.03). In men with SUVmean≥10, the PSA50-RR for LuPSMA vs. cabazitaxel were 32/35 (91%) vs. 14/30 (47%). In men with PSMA SUVmean < 10, the PSA50-RR were 33/64 (52%) vs. 23/71 (32%). High-volume metabolic disease on FDG PET (MTV ≥200mL) was seen in 30/99 (30%) assigned LuPSMA and 30/101 (30%) assigned cabazitaxel. The PSA50-RR in these men was 17/30 (57%) for LuPSMA vs. 6/30 (20%) for cabazitaxel. In comparison, the PSA50-RR for men with MTV < 200mL on FDG PET was 48/69 (70%) for LuPSMA vs. 31/71 (44%) for cabazitaxel. After accounting for treatment, the odds of a PSA50-response was lower among men with high MTV (OR 0.44; p = 0.01). The HR for PSA-PFS for LuPSMA vs cabazitaxel was 0.45 (95%CI 0.25-0.80) for SUVmean≥10 vs. 0.77 (95%CI 0.53-1.12) for SUVmean < 10 (p = 0.2). Findings were similar for rPFS. The HRs for high MTV on FDG PET adjusted for treatment were 1.44 (95%CI 1.03-2.02) for PSA-PFS (p = 0.03); and 1.79 (95%CI 1.28-2.52) for rPFS (p < 0.001). Conclusions: In men with mCRPC, PSMA SUVmean≥10 was predictive of a higher likelihood of favourable response to LuPSMA than cabazitaxel, whilst a high volume of disease on FDG PET was associated with a worse prognosis regardless of randomly assigned treatment. Clinical trial information: NCT03392428.

485 Background: In patients (pts) with muscle invasive bladder (MIBC) suitable for curative definitive chemoradiotherapy (CRT), we hypothesise that the addition of pembrolizumab may be safe and improve efficacy. A pre-planned safety analysis was performed after the first 10 of planned 30 pts were enrolled and completed treatment. Methods: Patients with maximally resected non-metastatic MIBC and ECOG 0-1, who desire bladder preservation or are ineligible for cystectomy were treated with 64Gy in 32 daily radiation fractions to the whole bladder alone over 6.5 weeks in combination with 6 concurrent doses of weekly cisplatin at 35mg/m2 IV. Pembrolizumab was commenced concurrently with radiation and given flat-dose 200mg IV q21 days for 7 doses. Surveillance cystoscopy, urine cytology and CT chest-abdomen-pelvis were performed 12 & 24 weeks post CRT. The primary endpoint is feasibility, defined by a satisfactory low rate of unacceptable toxicity of a) G3-4 non-urinary adverse events (AE) or b) failure of completion of planned CRT according to defined parameters. Secondary endpoints include complete cystoscopic response without metastatic disease at 12 & 24 weeks, loco-regional PFS, metastatic DFS, and overall survival. A 2-stage design was planned, with accrual to be halted if >5 of the first 10 pts experienced unacceptable toxicity up to 12 weeks post treatment. Results: All 10 pts completed the course of CRT and pembrolizumab without alteration in radiation dose or schedule. 1 patient had a dose of cisplatin withheld. 4/10 pts experienced G3-4 non-urinary adverse events within 12 weeks of completing treatment. One immune related AE interrupted pembrolizumab delivery (G2 nephritis). By week 24, 9/10 pts achieved a complete cystoscopic response to treatment post CRT and were free of distant metastatic disease. Conclusions: Interim results indicate that pembrolizumab and CRT shows satisfactory safety, and promising efficacy. There were no unexpected safety signals. Follow up of these and additional pts will better define the efficacy and safety of the combination. Enrolment is ongoing with 20 pts recruited out of a planned total of 30. Clinical trial information: NCT02662062.