We saw recently (see this link) that of chemo and hormonal medicines for metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third treatment after Taxotere (docetaxel) and Zytiga (abiraterone) or Xtandi (enzalutamide). But when should radiopharmaceuticals, either approved ones like Xofigo (Ra-223), or prospective ones like Lu-177-PSMA-617, be used in the optimal sequencing?
Michael Hofman reported the results of the TheraP randomized clinical trial (RCT). They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;
- mCRPC (PSA≥20 ng/ml and rising)
- must have had docetaxel
- must have had either Zytiga or Xtandi or both
- healthy, with good liver, kidney, and blood function
In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:
- Their metastases were insufficiently PSMA-avid - (10% excluded)
- There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
- 85 patients were treated with Jevtana
- 98 patients were treated with Lu-177-PSMA-617
The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:
- Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
- The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
- At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
- Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
- It is too early for data on overall survival
- Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% of those taking Jevtana
- The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, pain, nausea, dry mouth/eyes, low platelets, and anemia. Only 1 patient discontinued for toxicity.
- The most common adverse events reported by those taking Jevtana were fatigue, pain, diarrhea, nausea, loss of taste, neuropathy, dry mouth, and neutropenia, 3 patients discontinued for toxicity
Given the comparatively low toxicity, it seems like Lu-177-PSMA-617 should usually be the preferred third treatment, over Jevtana, although longer follow-up will be needed to see if there will be a survival difference.
This study further highlights the importance of getting both an FDG and a PSMA PET scan at about the same time. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.
PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:
- Should it be used soon after second-line hormonals?
- Should it be used before or soon after docetaxel?
- Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
- Should it be used in minimally metastatic patients?
- Should it be used in newly diagnosed metastatic patients?
- Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
- Will PARP inhibitors enhance the cell-kill rate?
- Is PSA the best biomarker of effectiveness?
- What are the best radionuclides to use (e.g., Ac-225, Th-227)?
- What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
- Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
- How do they compare to PSMA BiTE therapies?
- How does it compare to Xofigo for bone metastases?