Showing posts with label PSMA-617. Show all posts
Showing posts with label PSMA-617. Show all posts

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.

Monday, October 16, 2017

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, 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. reported 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, they had the following outcomes:
  • 67% of patients had some PSA decline
  • 33% of patients had a PSA decline of at least 50%
  • 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
So 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 they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.



Tuesday, September 5, 2017

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.

The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.

Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al.  at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.
  • In 56%, PSA decreased by at least 30%
  • In 33%, PSA decreased by at least 50%
  • In 11%, PSA decreased by at least 90%
  • Complete remission of metastases in 5%
  • Metastases stayed stable in 63%
  • Metastases progressed in 32%
  • Performance status was stable or improved in 74%
  • In those with bone pain, it was reduced partially or completely in 58%
  • Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
  • There were no severe (Grade 3 or 4) toxicities.
  • There was no kidney toxicity up to 40 GBq (see this link)
(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).
  • In 38%, PSA decreased by at least 50%
  • Median clinical progression-free survival was 4.1 months
  • Median overall survival was 12.9 months
  • Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)
A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

  • 68% of patients had some PSA decline
  • 37% of patients had a PSA decline of at least 50%
  • More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes

These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival

While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.

Readers may wish to read these other articles on this subject:

Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering




Thursday, December 22, 2016

Ac-225-PSMA-617 extends survival (update)

The nuclear medicine group at the University of Heidelberg recently reported a complete response in two patients treated with Ac-225-PSMA-617 (see this link). Now they have treated 80 patients with at least 24 weeks of follow-up, and report impressive results (here).

The 80 patients had failed on multiple therapies and were only expected to have 2-4 months of median survival.
  • The response rate (PSA reduction and tumor shrinkage) was 75%
  • Most were still alive 6 months after the therapy
  • Dry mouth was the only side effect of treatment
This is a report from a media release, and not a peer-reviewed journal. I will certainly report more details as they become available.

Anyone interested in medical tourism to try this experimental therapy can contact Dr. Haberkorn at the University of Heidelberg (he speaks English):
Email: Uwe_Haberkorn@med.uni-heidelberg.de
Phone: 06221 56-7731

There is a Phase 1 (dose finding) clinical trial of Ac-225-J591(a PSMA ligand) at Weill Cornell in NYC. It involves 8 visits over 12 weeks. Eligible patients must be metastatic and castration-resistant. They must have tried Zytiga, Xtandi and Taxotere or Jevtana. Scott Tagawa is the Principal Investigator.
Email: guonc@med.cornell. edu

(BTW - Scott Tagawa is also leading a trial combining two Lu-177-PSMA radiopharmaceuticals at Weill Cornell)

Wednesday, October 26, 2016

Lu-177-PSMA-617: Another update


Because there is great interest in systemic therapies for metastatic prostate cancer, I want to provide readers with the latest news about the Lu-177-PSMA-617 trials in Germany.

I recently reported (see this link) on 74 patients – 31% had PSA declines greater than 50%. A new report by Rahbar et al. expands the patient base to include PSA data on 99 patients and toxicity data on 121 patients treated at 12 therapy centers.  After median follow-up of 16 weeks, and up to 4 therapy cycles:
·      45% had a PSA decline greater than 50%
o   40% after a single cycle
·      18/121 patients (15%) had serious or life-threatening hematotoxicity, affecting red blood cells (10%), platelets (4%), and white blood cells (3%)
·      Xerostomia (loss of saliva) occurred in 8%

This is a very encouraging PSA response. For comparison, only 13% had a PSA reduction greater than 50% in the Xofigo clinical trial. However in that trial, 66% had a 50%+ decline in bone alkaline phosphatase, which may be a better biomarker for bone metastases. The hematotoxicity was identical.

What we really want to know is whether the treatment increases survival, and whether it is any better than Xofigo in doing so. The potential benefit of Lu-177-PSMA-617 is that it can treat non-osseous metastases too. We await future clinical trials to prove its benefit.


Friday, August 26, 2016

Lu-177-PSMA Update


One of the more important emerging radiotherapies for metastatic castrate-resistant prostate cancer is Lu-177 that is chemically bonded to a ligand -- an antibody or a small molecule that attaches to the prostate-specific membrane antigen (PSMA). We’ll call this class of medications Lu-177-PSMA. PSMA is expressed on the surface of 95% of all metastatic prostate cancer cells. See this link for a fuller explanation. Many of the studies on Lu-177-PSMA have been conducted in Germany. Recently, there was a report on a small study from Bad Berka, Germany with some early encouraging results. There have been a few more trial reports since then.

All of the more recently published studies used a ligand called PSMA-617, a small molecule that attaches to PSMA, rather than a PSMA antibody. It was hoped that this ligand would be more specific to prostate cancer cells, with less affinity for salivary glands and kidneys where it can cause side effects and false positives.

Kratchowil et al. at the University of Heidelberg reported on 30 patients treated with one to three cycles of Lu-177-PSMA-617.
  • ·      PSA decreased in 21/30 patients (70 percent).
o   PSA decreased by > 50% in 13/30 (43 percent)
o   Among 11 patients who had 3 cycles of therapy, 8 (73%) had PSA declines >50% that were sustained for over 24 weeks. Number and size of metastases decreased as well.
  • ·      Hematotoxicity (from bone marrow suppression) was mild.
  • ·      Xerostomia (dry mouth), nausea and fatigue were transient and occurred in <10 percent.
  • ·      Excess radioactivity was cleared from the kidneys within 48 hours.
Rahbar et al. at the University Hospital M√ľnster reported on 74 patients treated with a single dose of Lu-177-PSMA-617.
  • ·      PSA decreased in 47/74 patients (64 percent).
o   PSA decreased by > 50% in 23/74 patients (31%)
  • ·      PSA was stable (- 50% to +25%) in 35/74 patients (47%)
  • ·      PSA increased by > 25% in 17/74 patients (23%)
  • ·      No significant loss of red blood cells, white blood cells or kidney function
  • ·      Mild decline in platelets, but within normal range

Rahbar et al. also report outcomes on 28 patients after one vs. two treatments.
  • ·      PSA decreased in 59% of patients after 1 treatment and in 75 percent after 2 treatments.
o   PSA decreased by > 50% in 32 percent of patients after 1 treatment and in 50% after 2 treatments.
  • ·      Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
  • ·      No clinically significant or lasting toxicity occurred.

Radiotherapy with Lu-177, though encouraging, is still in its early days. There is much work to be done in identifying the optimal ligand, optimal dose, optimal number of treatments, optimal patient/disease characteristics, and adjuvant therapies. I encourage participation in clinical trials in the US (NCT00859781) and in Germany.