First clinical trial of Lu-177-PSMA-617 in recurrent, hormone-sensitive men

While we expect only a few months of extra survival from the VISION trial of Lu-177-PSMA-617 in heavily pretreated, metastatic, castration-resistant men (see this link), we hope to get more out of the radiopharmaceutical if used earlier. Privé et al. reported the results of a pilot trial in 10 recurrent men treated with Lu-177-PSMA-617 at Radboud University in Nijmegen, The Netherlands. They were all:

• Recurrent after prostatectomy ± salvage radiation (PSA>0.2 ng/ml) 
• Rapid PSA doubling time (< 6 months)
• Between 1-10 metastases detectable on a PSMA PET scan or USPIO MRI
• At least 1 metastasis > 1 cm.
• Unable to receive SBRT to metastases 
• No visceral metastases 
• Have not begun salvage ADT
• Treated with a low dose (3 GBq) on day 1; second treatment (~6 GBq) after 8 weeks (compared to dose in VISION trial of 7.4 GBq in each of 4-6 cycles)

After 24 weeks of follow-up after Cycle 2:

• 5 patients had PSA reduced by >50% (1 undetectable)
• 2 patients had stable PSA
• 3 patients had PSA progression
• 6 patients had a radiographic response
• 4 patients had radiographic progression
• ADT-deferred survival was 9.5 months (median)
• Those with lymph node only metastases had the best response
• Those with any bone metastases had lesser response

After 2nd dose, comparing their 24-week PSA to their 12-week PSA:

• PSA was continuing to decline in 3 patients
• PSA was rising again in 6 patients

Side effects were mild (no grade 3) and transient:

• fatigue in 7; nausea in 3
• dry mouth (xerostomia) in 2

There are lots more questions than answers:

• Would a higher dose and more treatments be more effective?
• Would a higher dose and more treatments be more toxic?
• Is it like Xofigo in that it's more effective with micrometatases? If so, would a combination with SBRT targeted at the larger metastases be more effective?
• Since it was more effective on lymph nodes, would it make a good combination with Xofigo for patients who have both lymph node and bone metastases? (See also Th-227-PSMA)
• Because there seems to be a continued abscopal effect for some patients, would combining it with Provenge be optimal?
• Would pretreatment with ADT or a new anti-androgen (Xtandi, Erleada or Nubeqa) increase expression of PSMA, and increase radiosensitivity?
• Can we predict who will benefit?
• Use in other patient populations remains to be explored: high-risk, newly diagnosed metastatic, castration-resistant but chemo-naive. Optimal sequencing with other therapies remains to be explored.

PSMA-targeted radiopharmaceutical clinical trials in the US

(frequently updated)

Now that the VISION trial of Lu-177-PSMA-617 is no longer recruiting, some patients are wondering if they can still get PSMA-targeted radiopharmaceuticals in the US, without traveling to Germany, Australia, India, etc. Here is a list of trials that are active, still open to recruitment, or will soon be recruiting. 

Unless otherwise noted, they are all for men who are: 

• metastatic
• castration-resistant 
• have had at least one taxane chemotherapy
• at least one of the advanced androgen receptor therapies (e.g., Zytiga, Xtandi, Erleada, or Nubeqa)
• no Xofigo
• PSMA-avid on a PSMA PET/CT scan

Radiopharmaceutical	Adjuvant drugs	Extra criteria	Recruitment status/ contact	Locations
Ac-225-PSMA-R2		•After or without prior Lu-177-PSMA	Begins 10/23	TBD
Lu-177-PSMA-617 PSMACare	1. ADT 2.ARSi+ADT (ARSi=Zytiga, Xtandi,Erleada or Nubeqa)	•Metastatic with PSMA PET, but not with conventional imaging •CRPC •No prior ARSi or chemo	Begins 12/23	TBD
Lu-177-PNT2002 LUNAR	Before SBRT	Recurrent and oligometastatic	recruiting	UCLA
Lu-177-rhPSMA-10.1		±previous chemo	recruiting	•Maryland •St.Louis •Omaha •Mt Sinai-NYC
Lu-177-PSMA-I&T		Chemo naïve, failed one hormonal	recruiting	• 58 locations
Ac-225-PSMA-I&T TATCIST			Recruiting	• Houston
Ac-225-J591			recruiting	• Weill Cornell • Brooklyn Methodist
Pluvicto+ONC392 (a CTL4 blocking immunotherapy)			Begins 9/23	• NYU Langone • Columbia • Maryland • Omaha • Duke • UTSW (Dallas) •UWisc. Carbone
Ac-225-J591 + Lu-177-PSMA- I&T			Suspended	• Weill Cornell • Brooklyn Methodist
Ac-225-J591	Keytruda	No chemo since castration resistant	recruiting	• Weill Cornell • Brooklyn Methodist • Dana Farber • Columbia
Cu-67-SAR-bisPSMA SECuRE		Previous chemo OK, not required	recruiting	• Johns Hopkins •Mayo Rochester •Mayo, AZ •Tulane, N.O. •Barnes Jewish, St. Louis •Omaha, NE •Weill Cornell
Lu-177-PSMA-617 PSMAddition		mHSPC (M1 or N1) Treatment naive	Recruiting	• 188 sites
Lu-177-PSMA-617	Keytruda	No chemo since castration resistant	active, not recruiting	UCSF
Lu-177-CTT1403		No Jevtana	active, not recruiting	UCSF
Lu-177-PSMA-617			Active, not recruiting	•Weill Cornell •Tulane
Th-227-Antibody (see article)			active, not recruiting	• Royal Marsden (UK) • Finland • Tulane • MSK • Omaha, NE
Lu-177-J591	Ketoconazole	Prior RP or RT CRPC Non-metastatic	active, not recruiting	• Weill Cornell • USC • Georgetown • IU • U of Iowa • UPMC
Lu-177-PSMA-R2			Active, not recruiting	• Stanford • Yale • Tulane • Johns Hopkins • Mt Sinai • MD Anderson • U of Wisconsin • Phoenix
Lu-177-PSMA-617 PSMAfore		Chemo and immunotherapy naïve, failed one hormonal	Active, not recruiting (Phase 3 RCT)	• 72  sites
Lu-177-PSMA-617 (VISION)			Active, not recruiting	• 84 locations Results expected August 2020
I-131-1095-MIPS (see article)	Xtandi	Chemo naïve Failed Zytiga	Active, not recruiting	• 17 locations Results expected December 2021

Lu-177-PSMA-617 vs Jevtana (cabazitaxel): which should I do next?

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

Michael Hofman reported the results of the 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;

• mCRPC (PSA≥20 ng/ml and rising)
• must have had docetaxel
• must have had either Zytiga or Xtandi or both
• 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% excluded)
• There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
• 85 patients were treated with Jevtana
• 98 patients were treated with Lu-177-PSMA-617

The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:

• Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
• The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
• At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
• Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
• It is too early for data on overall survival
• Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% 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 1 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, 3 patients discontinued for toxicity

Given the comparatively low toxicity, it seems like Lu-177-PSMA-617 should usually be the preferred third 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. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals 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 hormonals?
• 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?
• 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)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases?