Ac-225-PSMA-617 in mCRPC: an update

We now have some details from clinical trials of the radiopharmaceutical actinium-225-PSMA-617 (Ac-225-PSMA-617) in very advanced prostate cancer patients.

Kratchowil et al. have reported on 40 patients who received this treatment at the University of Heidelberg. All patients had progressed after multiple prior therapies and were expected to have a median projected survival of 2 to 4 months (see this link) at time of treatment. They received three cycles of Ac-225-PSMA-617 in 2-month intervals.

  • 11 patients did not complete the three cycles:
    • 5 discontinued due to non-response.
    • 4 discontinued due to xerostomia (dry mouth).
    • 2 did not survive 8 weeks.

However, among the 38 surviving patients:

  • 87 percent had some PSA decline.
  • 63 percent had a PSA decline of > 50 percent from baseline.
  • Tumor control lasted for an average (median) of 9.0 months.
  • 5/38 patients (13 percent) had a response lasting > 2 years.
  • The patients’ previous therapies with abiraterone had lasted for 10.0 months, with docetaxel for 6.5 months, with enzalutamide for 6.5 months, and with cabazitaxel for 6.0 months.

These outcomes are impressive for a therapy given when all other therapies have failed.

It is unclear whether Ac-225-PSMA is better than radium-223 acetate (Xofigo), the most effective of the radiopharmaceuticals approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). But Xofigo only attacks cancer in bones, whereas Ac-225-PSMA-617 attacks prostate cancer anywhere in the body. (Older radiopharmaceuticals like strontium-89 chloride/Metastron could only relieve pain and had no survival benefit.)

As of late 2016, the Heidelberg group had treated a total of 80 patients with this agent.

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

9 Responses

  1. The resuts are impressive. When comparing radium-223 treatment with actinium radio-ligand therapy (Ac-RLT), it is important to recall that radium-223 is only a treatment for bone metastases whereas Ac-RLT is a treatment of PSMA positive lesions whether they are bone metastases or visceral metastases.

    The important question is actually how Ac-RLT works relative to Lu-RLT. The two forms of RLT might differ in toxicity but less in efficacy.

    The authors should be complimented for the information given for duration of previous treatments with established life-prolonging drugs. For these drugs, efficacy goes down when the drugs is given later in the sequence of treatment, for instance comparing third-line treatment with second-line treatment. So the information of response duration adds to the thoughts of the proper place of RLT in the landscape of all available treatments for mCRPC.

  2. How does Ac-225-PSMA compare to lutetium-177 PSMA, Allen?

    One of our guys is about to start Lu-177 in LA this coming week.

  3. Rick,

    There’s never been a head-to-head comparison, as far as I know. These trials are small and the patient profiles can vary a lot from study to study. All I can tell you is that in the latest Lu-177-PSMA meta-analysis, Lu-177-PSMA elicited some PSA response in 68% and at least 50% PSA reduction in 37%, but that responses varied widely. The trade-off is that Lu-177 is a beta emitter with a longer range and less power, whereas Ac-225 is an alpha emitter with short range and more power.

    The other radiopharmaceutical of interest is I-131-MIP-1095 (currently in a dose-finding trial at MSKCC). It elicited some PSA response in 84% and at least 50% PSA reduction in 61%. I-131 is an even longer range beta emitter than Lu-177, and because it is strongly bonded to the ligand (not just chelated), it seems to have a higher effective dose.

  4. I want to be among the first “guinea pigs” for early metastatic prostate cancer.

    I had a robot-assisted laparoscopic prostatectomy (RALP) on 07/31/18, Gleason 4 + 3, clear margins, bilateral nerve-sparing, perineural invasion (PNI), seminal vesicle invasion (SVI), three of 30 lymph nodes involved, clinical stage T3b My PSA at 6 weeks post-surgery was 0.38, and has continued to rise since.

    I Have not done salvage radiation nor ADT. I had a PSMA scan at UCLA on 05/30/19, identified a possible metastatic iliac lymph node. This was surgically removed on 07/30/19, but pathology found no cancer. My PSA rose again after this second surgery, and is currently 1.24 ng/ml. My oncologist wants me on ADT; I don’t since it’s not likely to be curative and I can’t abide the side effects.

    I am absolutely convinced this new technology using PSMA with Ac-225 has an excellent chance to completely kill off the residual cancer without the nasty effects of androgen xeprivation therapy (ADT) and eventually chemotherapy. How can I submit myself for a trial for early metastatic prostate cancer? I know currently most of these trials are for men who’ve already done radiation, ADT, chemotherapy, etc., but my philosophy is, why mess around with treatments that will only delay onset, not cure me?

    I’m very healthy otherwise and I believe I have an excellent chance of a complete cure with this new technique. I’m willing to sign waivers re: any possible side effects or long-term consequences and willing to agree not to sue or hold anyone responsible regardless of outcome. Please let me know who I can contact to initiate this. Also might be willing to travel to Germany for this treatment if it’s easier to get into a study or approved treatment.

    Thx sincerely.

    Chris I Kirkendall
    Wheeling, IL USA

  5. Dear Chris:

    First, there seems to be a problem, which is that the PSMA scan you had identified an area of risk that turned out to be a false positive for prostate cancer. In other words, despite your rising PSA level, there is no evidence yet that you actually have metastatic prostate cancer.

    Second, as far as I am aware, to date, all trials of Ac-225 PSMa have been conducted in men with disease that is much more advanced than yours (see for example here and here).

    Also — again in so far as I am aware — your only potential opportunity would be for you and your doctor to approach the manufacturers of actinim-225 PSMA (Endocyte, which was recenty acquired by Novartis) and talk directly to someone associated with that company. However, I have to tell you that I suspect your chances of being able to get treatment with this investigational drug at your stage of disease are extremely low at this time.

  6. Salvage radiation to the entire pelvic lymph node area with long-term ADT was found to be beneficial in this retrospective study.

  7. Thx for the response.

    An update — Most recent PSA in November rose sharply to 3.08. I had an Axumin PET scan in December which identified two apparent lymph node metastases. I will have one of these treated with targeted radiation therapy within the next couple weeks; going for a pre-scan on Tues 01/14/20. I’m not interested in pelvic radiation, probably wouldn’t do me much good at this point, sort of like closing the barn door after the horse got out. Trying to avoid ADT, it’s not for me — it won’t cure me and will seriously degrade my QOL, and from everything I’ve read would only add about 1.8 years. I’d rather live my remaining time with decent QOL, especially if my long-term outcome will be the same, but just a couple years down the road. My only hope really is the Ac-225 PSMA. I’m hopeful that someone in Germany will accept me.

  8. Dear Chris:

    While many will understand your dislike of ADT, I do think you are seriously underestimating its potential impact on your long-term survival and you also need to appreciate that the adverse effects of ADT are relatively minor for many men. Responses to ADT — both positive and negative — are highly individual. The only way to know how you might respond is to actually try the drugs.

    Obviously, all decisions are up to you, but you might want to talk to your doctors about a short course of ADT to see if (a) it drops your PSA level into the undetectable range and (b) it does this without any significant side effects. At the present you seem to be writing off a potentially highly effective form of treatment based on some assumptions that may not be true in your individual case.

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