Pluvicto+Xtandi Delays Progression Better than Xtandi-alone in mCRPC

Both Pluvicto (177LuPSMA-617) and Xtandi (enzalutamide) have been separately shown to delay progression and extend survival among metastatic and castration-resistant men with prostate cancer (mCRPC). Because they inhibit prostate cancer in different ways, it was hoped that combining them would have an additive benefit. In a clinical trial, enzalutamide temporarily increased expression of PSMA, so a synergistic effect is possible.

Emmett et al. reported the first results of the ENZA-p trial. 162 mCRPC patients with 2 or more risk factors were treated at 15 hospitals in Australia. Unlike the VISION trial, they did not previously receive docetaxel or 2nd line hormonal treatment for mCRPC. The risk factors were:

1. metastatic at original diagnosis
2. elevated LDH, ALP, albumin (PSA> 5 ng/ml)
3. PSADT< 84 days
4. < 3 years since diagnosis
5. ≥5 bone or visceral metastases 
6. pain requiring opiates
7. received abiraterone for mHSPC (docetaxel for mHSPC was allowed)

After 20 months of follow-up, the outcomes were:

• Median PSA Progression-Free Survival was 13.0 months for the combo vs 7.8 months for enza-only
• Median Radiographic Progression-Free Survival was 16 months for the combo vs 12 months for enza-only
• Percent with >50% PSA reduction was 93% for the combo vs 68% for enza-only
• Percent with >90% PSA reduction was 78% for the combo vs 37% for enza-only
• Too early for overall survival
• Improvement in pain scores were 61% for the combo vs 27% for enza-only
• Side effects for the combo vs enza-only were fatigue (75% vs 70%), nausea (47% vs 27%), and dry mouth (40% vs 10%).
• 81% received all 4 doses of Pluvicto.

Based on these results, and pending later follow-up on overall survival, Pluvicto should be combined with enza.

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