Does Lu-177-PSMA-617 increase survival?


We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA levels, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that increase survival.

Rahbar et al. have just reported data on the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles of treatment with Lu-177-PSMA-617, they had the following outcomes:

  • 67 percent of patients had some PSA decline
  • 33 percent of patients had a PSA decline of at least 50 percent from baseline
  • Median overall survival was 56 weeks (13 months)

The authors conclude:

177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide.

But is this conclusion justified? It’s hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC.

In the “ALSYMPCA” trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:

  • 14 months with Xofigo
  • 11 months with placebo

The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival. There have been a couple of small trials of “third-line” medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

  • 9 months with cabazitaxel

In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

  • 5 months with enzalutamide

These data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when data come from trials in which patients have not been randomized to differing treatment options. Certainly, there is enough suggestive data to warrant a Phase III randomized clinical trial of Lu-177-PSMA-617 .

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

7 Responses

  1. I am sorry to read of these comments. Basically what oncologists can prove when treating end-stage patients with cancer is to show efficacy. You do not expect a study of treating patients where all life prolonging treatments have failed — to increase overall survival substantially. With an experimental treatment like Lu RLT furthermore the concern has been to provide a safe treatment for palliation. So the dose has not been examined for the dose with the best efficacy. We need such knowledge prior to randomized trials with overall survival as endpoint or with with PSA decline more than 50% as surrogate endpoint.

    Further, with increasing use at many institutions we need clear reasoning of how we go on making progress for prostate cancer and reducing mortality for high-risk patients. So many patients die of prostate cancer so please do not let fuzzy logic hinder ambitious thinking to make the best of what we have.

  2. I guess my question about this is simple: Will this help a man with Stage IV, metastatic prostate cancer? He was diagnosed 5 years ago and I am seeing him deteriorate. There appear to be no more treatment options for the cancer other than continuing the Lupron injections and meds to help keep his plumbing working.

    Please advise.

    Thank you!
    Concerned wife / Ellen

  3. Hi Allen,

    It is obvious now that lutetium PSMA is not going to be a cure for castrate-resistant prostate cancer but it may play a useful role in slowing down the disease progress. It was interesting in this study that the patients who had received more treatments had a longer survival time, although obviously many patients didn’t live long enough to receive the third and fourth treatments. It does make me wonder whether the place for this treatment is much earlier in the course of the disease, given that the treatment toxicity appears to be very low.

    Regards,

    John Whittle

  4. Dear Ellen:

    Alas, it is impossible to be able to tell beforehand whether any drug is going to be able to “help” any one individual patient. There are far too many variables that affect the activity of each drug in each patient.

    What I can tell you, and what does seem to be confirmed by this paper and by reports from individual patients, is that 177Lu-PSMA-617 does have beneficial effects for many patients who have been treated with this agent … but those effects are not long-lasting. We are not seeing men with metastatic, castration-resistant prostate cancer who get treated with 177Lu-PSMA-617 go into complete, long-term remissions.

    Thus the degree to which treatments of this type can “help” any one individual patient may depend on the goals of those individual patients as well as how well he responds to treatment with the drug.

    It also needs to be born in mind that for some patients the issue is not whether 177Lu-PSMA-617 actually “works” for them, it is about whether they have tried all the available options.

  5. John,

    I very much agree. The patients in this study were “heavily pretreated” (including chemo + Zytiga and/or Xtandi) and had few options. We could learn a lot from a head-to-head trial against Xofigo (all patients here at least had bone metastases) — perhaps that will be done in a Phase III trial someday. And I also agree that the association between number of cycles vs survival may be a reverse cause/effect relation — who knows?

    The ongoing US trial among non-metastatic CRPC patients (NCT00859781), who are undoubtedly in an earlier stage of progression, will be interesting. It is a rare subset, however. The dose-finding study at Weill Cornell (NCT03042468) has the same “heavily pretreated” requirements as this University Hospital of Muenster study. There is a dose-finding trial at MSKCC (NCT03030885) among men with mCRPC that doesn’t require pretreatment with a taxane or an advanced hormonal agent. There is also a dose-finding trial for mCRPC in Houston (NCT03042312) with no heavy pretreatment requirements — but it is very costly!

  6. We also have a trial at Zentralklinik Bad Berka looking at patients with LNM only. Results are very promising.

    Finn Edler von Eyben

  7. Thank you all.

    IF this would even slow down the progression for my husband, I would want him to have the treatment. I’d pretty much take him anywhere if there were a chance in helping him to live longer — providing it did not cause him unnecessary pain. My husband has gone through 40 rounds of radiation and has been on Zytiga and Xtandi and docataxel and cabazataxel (Jevtana) — and after the third dose of cabazataxel he had major hallucinations and saw things that no one else could see — bad time. He’s had Provenge as well. Now it’s down to a Lupron injection every 6 months; Flomax 2x per day; Lasiks 2x per day; and potassium 2x per day. They have also prescribed other meds for memory and then another drug to keep him “calm” (antipsychotic) though I have to add – the only time he became psychotic was directly after the third dose of cabazataxel; … he was fine on Monday before the infusion — and during and afterwards; I noticed he was not behaving like his typical calm and easy-going self — he was becoming quite agitated, if you will, that turned into a nightmare by Wednesday. He was in the hospital for quite a while that time (add to the issue at the time — cellulitis; edema; and lymphodema). SO, as you can read, he’s been through a lot.

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