Saturday, January 13, 2018

Ac-225-PSMA-617 (update)

We now have some details of the clinical trial of Ac-225-PSMA-617 in advanced prostate cancer patients. Kratchowil et al. reported on 40 patients who received this treatment at the University of Heidelberg. All patients had failed multiple therapies and were expected to have 2-4 months median survival (see this link). They received 3 cycles of Ac-225-PSMA in two-month intervals.

  • 11 patients did not complete 3 cycles
    • 5 discontinued due to non-response
    • 4 discontinued due to xerostomia (dry mouth)
    • 2 did not survive 8 weeks.
Among the 38 surviving patients:
  • 87% had some PSA decline
  • 63% had a PSA decline greater than 50%
  • Tumor control lasted 9.0 months (median)
  • 5 patients had a response lasting more than 2 years
  • Previous therapies with abiraterone lasted 10.0 months, docetaxel lasted for 6.5 months, enzalutamide for 6.5 months, and cabazitaxel for 6.0 months

These outcomes are impressive for a therapy given when all other therapies have failed. It is unclear whether it is better than Xofigo, the only approved radiopharmaceutical for metastatic castration-resistant prostate cancer. Xofigo only attacks cancer in bones, whereas Ac-225-PSMA attacks prostate cancer anywhere in the body.

(Update 5/19/2019)

Sathekge et al. reported the outcomes on 73 mostly chemotherapy-naive and abiraterone/enzalutamide-naive metastatic castration-resistant patients treated with Ac-225-PSMA-617 in South Africa. Most patients had 3 treatment cycles (every 2 months). Subsequent doses were lower to prevent side effects. PSA and metastatic activity was tracked using Ga-68-PSMA-617 PET scans.
  • 83% of patients responded to treatment
  • in 70% of patients, PSA declined by over 50%
  • PSA declines of over 50% predicted longer progression-free survival and overall survival
  • In 29% of patients, all lesions disappeared
  • During follow-up, 23 patients (32%) had disease progression and 13 (18%) died of prostate cancer
  • Progression-free survival was 15 months (median)
  • Overall survival was 18 months
  • Xerostomia (dry mouth) occurred in all 85% of patients, but it was not severe enough to stop treatment
  • Anemia occurred in 27 patients (37%); none grade 4
  • Grade 3 or 4 renal toxicity occurred in 5 patients with pre-existing renal impairment
This study suggests that Ac-225-PSMA-617 can be beneficial in patients who have not been heavily pre-treated. It also shows that xerostomia can be mitigated by reducing the subsequent doses given, and that for most patients, side effects are not severe enough to stop treatment. Lu-177-PSMA is now in a Phase 3 clinical trial at multiple sites in the US.


  1. I think this looks quite good to me. I would hope that they would find a way to protect the saliva glands, possibly by a local injection of something that binds to the PMSA, such as J591, or a small molecule designed for the job.

    1. See the most recent (9/21/18) update for a strategy for reducing the effect on salivary glands. A recent study used sialendoscopy with dilatation, saline irrigation and steroid injection to preserve salivary function:

  2. I assume that they have thought of 223Ra+PSMA and found it to be unworkable.

    1. Ra-223 has not attached well to PSMA ligands so far.

  3. I know that they are continuously working on the salivary gland issue. Most patients carry water with all times. There are gels and pillules available at the pharmacy but the effect of these seem don't seem to be that great. Xerostomia is also caused by another diseas (I don't recall the name). My husband uses glycerine at night before bedtime so that he does have to wake up to drink water. So he manages it by eating juicy foods like fruit and salads and the occasional soup or stew for dinner. I believe most of the patients will not stop treatment just because of this. We have seen excellent results after 2 injections.

  4. Telix Pharmaceuticals has recently announced completion of a phase II trial that shows low but frequent doses of their 177Lu-huJ591 can be effective "with no irradiation of salivary and lacrimal glands."

    then select 26th Apr 2019 announcement.

    Also researchers in Vancouver are experimenting with MSG (yes the food additive) to reduce damage to salivary grands during radio-pharmaceutical treatment in animal models.