THE "NEW" PROSTATE CANCER INFOLINK

We saw recently (see this link) that of chemotherapeutic and hormonal medicines for treatment of metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third-line treatment after Taxotere (docetaxel) and Zytiga (abiraterone acetate) or Xtandi (enzalutamide). But when should radiopharmaceuticals — either approved ones like Xofigo (radium-223), or prospective ones (like Lu-177-PSMA-617) — be used in the optimal sequencing?

Hofman et al. have now reported the results of the Phase II 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:

• Must have mCRPC (PSA≥20 ng/ml and rising)
• Must have had docetaxel
• Must have had either Zytiga or Xtandi or both
• Must have been otherwise 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 percent excluded)
• There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) (18 percent excluded)

Of the 200 patients actually eligible for study treatment,

• 85/101 patients were treated with Jevtana
• 98/99 patients were treated with Lu-177-PSMA-617

The endpoint used was the percentage of patients whose PSA declined by at least 50 percent (PSA50) from baseline after the treatment.

After a median follow-up of 13 months:

• Lu-177-PSMA-617 had a PSA50 of 66 pecent vs 37 percent for Jevtana.
• PSA progression occurred in 31 percent fewer patients among those treated with Lu-177-PSMA-617 relative to those treated with Jevtana.

At 12 months of follow-up,

• Progression-free survival was 19 percent for Lu-177-PSMA-617 vs 3 percent for Jevtana
• Pain improvement was better for Lu-177-PSMA-617 (60 percent) than Jevtana (43 percent).

It is too early for data on overall survival.

Serious/life-threatening adverse events occurred in 33 percent of those taking Lu-177-PSMA-617 vs. 53 percent 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 one 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. Three patients discontinued for toxicity.

Given the comparatively low toxicity, it seems like Lu-177-PSMA-617 should usually be the preferred third-line 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.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. PSMA expression increases as metastases develop, reaches a peak, and then decreases. PSMA expression also increases when second-line hormonal agents 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 hormonal agents?
• 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 (if this is clinically possible)?
• 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, bombesin, uPAR)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases?

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: cabazitaxel, Jevtana, Lu-177-PSMA-617, mCRPC |