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.

Whole gland TULSA-PRO and HIFU outcomes: Is it time to give up on thermal ablation for prostate cancer?

 We have seen that there are many unanswered questions about focal thermal ablation (see this link), among them are:

1. Is Index Tumor Theory valid?
2. Can foci of cancer be precisely targeted using current imaging methods?
3. Does thermal ablation completely ablate the cancer in the ablation zone?
4. Will the Heat Sink Effect and biochemical protective mechanisms (e.g., heat shock proteins) always cause sub-lethal killing?
5. Is toxicity and damage to organs at risk any better than radical (whole gland) radiation?
6. How do the high "re-do" rates affect toxicity and costs?
7. How do we track success?
8. What are the best salvage therapies?
9. Can it extend the time on active surveillance?
10. What are the intra-operative risks?
11. What is the learning curve like for therapists?
12. Is it worth the cost?

Laurence Klotz et al. conducted a clinical trial of a new kind of high-intensity focused ultrasound (HIFU). He studied whole-gland ablation because current FDA rules only permit ablation for removal of prostate tissue (like a TURP), but not for treatment of prostate cancer. In fact, the FDA specifically rejected HIFU for the treatment of prostate cancer. 

TULSA-PRO utilizes a thermal feedback loop to assure that tissue temperature reaches the desired heating. It is done "in-bore" in an MRI by a team consisting of a urologist and an interventional radiologist, and an anesthesiologist (full anesthesia was required). It was hoped that the MRI precision and assured tissue heating (to 55°C) would afford higher cancer-killing with less toxicity.

115 patients were carefully selected:

• 15% were low volume GS 3+3 (cancer in ≤2 cores, <50% in any core)
• 23% were high-volume GS 3+3
• 60% were GS 3+4
• 3% were GS> 3+4
• 94% were T1c or T2a
• Median PSA=6.3
• 67% were intermediate risk (predominantly favorable)
• 33% were low-risk
• Median prostate volume was 40 cc.

The operative procedure involved:

• prophylactic antibiotics
• general anesthesia
• cystoscopy
• transurethral US heating wand
• pelvic tissue at apex avoided to avoid incontinence
• endorectal cooling device
• 243 minutes (4 hours), start to finish
• suprapubic catheter (17 days)

Safety Outcomes/ Adverse Events:

Physician-reported outcomes:

• Acute (immediate) Grade 2:
• erectile dysfunction (29%)
• UTI (25%)
• bladder spasm (10%)
• painful urination (10%)
• urinary retension (8%)
• pain (7%)
• incontinence (6%)
• epidydimitis (5%)
• Acute (immediate) Grade 3 (severe, requiring intervention):
• infection (4%)
• urethral stricture (2%)
• urinary retention (1.7%)
• urethral calculus and pain (1%)
• urinoma (1%)
• long-lasting Grade 2 adverse events:
• erectile dysfunction (23%)
• incontinence (3%)
• recurrent infections (2%)

Patient-reported outcomes at 12 months vs baseline on EPIC questionnaire (% reporting moderate decline/ % reporting moderate gain):

• Sexual domain: 32%/ 1%
• ED on IIEF-15 questionnaire: 35%/6%
• 75% of previously potent men returned to erections sufficient for penetration with only ED meds.
• Urinary incontinence:14%/7%
• Urinary irritation/obstruction: 8%/5%
• Bowel domain: 5%/2%

Oncologic Outcomes (at 12 months):

• 35% had residual cancer at biopsy
• 24% among low volume GS 6
• 38% among high volume GS 6
• 37% among GS 3+4
• Median PSA reduced to 0.5 ng/ml
• Median prostate volume reduced to 2.8 cc
• PIRADS ≥3: 30%

There is little 12-month data available for other therapies, but recurrence rates almost always increase with time. There was a 2-year study of SBRT at Georgetown that may be roughly comparable:

	TULSA-PRO (1 year) 115 patients	SBRT (2 years) 100 patients
Risk category Low-risk Intermediate-risk High-risk	33% 67%	37% 55%  8%
Biochemical recurrence-free survival	100%	99% (1 local recurrence in a high-risk patient)
Biopsy-proven local recurrence	35%	1% estimated in the high-risk patient
Nadir PSA	0.5 ng/ml	0.5 ng/ml
Acute urinary toxicity (grade 3)	8%	0%
Acute rectal toxicity (grade 3)	0%	0%
Late-term urinary toxicity (grade 2+)	5%	18%  (1% Grade 3)
Late-term rectal toxicity (grade 2+)	0%	0%
Potency preservation among previously potent men	75%	79%

Full-gland TULSA-PRO seems to treat PSA without eradicating the cancer (see this link). In about a third of favorable-risk patients, the cancer remained viable in spite of the thermal ablation. We see that compared to whole-gland SBRT, it is less curative, Severe (requiring intervention) acute urinary toxicity is higher with TULSA-PRO, although late-term Grade 2 urinary toxicity is lower (not severe for either therapy). Rectal toxicity is not an issue for either therapy. Potency preservation is good and about equal for both.

15-year study suggests long-term inferiority

Bründl et al. reported 15-year oncological outcomes of 674 patients treated with whole-gland HIFU at one university hospital in Regensberg, Germany. Notably, overall survival and prostate cancer-specific survival were high in all localized risk categories. However, comparing 15-year prostate cancer-specific survival to similar risk men who have undergone prostatectomy at Memorial Sloan Kettering, we see the survival is relatively poor:

15-yr Prostate Cancer-Specific Survival

Risk Group	HIFU	RP*
Low Risk	95%	99%
Intermediate Risk	89%	98%
High Risk	65%	88%

* from the MSK pre-prostatectomy nomogram for a 62 yo man. For low-risk, he had PSA=5, GS 3+3, stage T1c, and 25% positive cores; For intermediate-risk, he had PSA=15, GS 4+3, stage T2c, and 50% positive cores; for high risk, he had PSA=25, GS 4+5, stage T3a and 100% positive cores.

The longest follow-up study there is for SBRT is 12 years. For SBRT, Alan Katz reported rates of "local control" on SBRT - the percent of patients who had recurrences only in the prostate. These could all theoretically be cured with a re-do of SBRT, focal brachytherapy or focal ablation. We can look at long-term local control from SBRT next to the long-term reported rates of salvage therapy after whole-gland HIFU (either re-do of HIFU or other salvage). HIFU does not compare well:

% patients who do not require salvage treatment

Risk Group	HIFU	SBRT
Low Risk	77%	97%
Intermediate Risk	52%	92%
High Risk	28%	88%

It is hard to see why anyone would choose HIFU or TULSA-PRO over SBRT. While focal ablation may incur less toxicity, the local recurrence rate will be much higher. These trials suggest that  HIFU and TULSA-PRO are inferior, although only a direct randomized comparison could prove that definitively.

For an article discussing the use of focal ablation as an active surveillance "extender," see:

What should focal therapy be compared to and how does it compare?

For an article discussing salvage focal ablation after the failure of radiation therapy, see:

Focal salvage ablation for radio-recurrent prostate cancer

Xofigo 2.0

(updated)

Xofigo (Radium 223 dichloride) is a systemic radiopharmaceutical. Radium is chemically similar to calcium and is taken up by bones in places where bone is actively growing, as in prostate cancer bone metastases. Radium 223 emits powerful alpha radiation that kills the cancer cells in the bone metastases. It has been found to double 2-year survival (see this link), extending survival time and reduce the skeletal-related events by almost a third. It often will not reduce PSA or show bone metastases shrinking in imaging, which some patients find disappointing.

It is FDA-approved for castration-resistant men with painful bone metastases, who do not show evidence of visceral metastases on a CT or MRI  (lymph node metastases are allowed). So far, it is only FDA-approved as a monotherapy, but researchers have wondered whether it may be more effective in combination with other medicines, or used in other situations.

Predicting successful treatment

NaF18 PET predicts Xofigo success (see this link). NaF18 PET is twice as sensitive for finding bone metastases compared to PSMA PET indicators (see this link).

Always use with a bone-preserving agent

Hijab et al. reported the results of the REASSURE trial.  They compared the bone fracture rate of 36 mCRPC patients who took Xofigo to a matched reference cohort of 36 mCRPC who didn't take Xofigo. They were all assessed for fracturesat baseline, 3 times during treatment and every 3 months thereafter with whole-body mpMRI. Very few (2-4 in each cohort) took a bone-strengthening agent. After 16 months of follow-up, they found:

• 56% had new fractures
• 3.7 fractures per patient with fractures
• 13.6 months to first new fracture
• ⅔ of new fractures were in the spine
• Only ⅓ were at sites of metastases
• Half the fractures were asymptomatic (no pain)
• No association of Xofigo dose with risk of fracture
• Higher # of bone metastases, high ALP, and previous use of steroids were associated with higher risk of fractures.

In the reference cohort (mostly using Zytiga or Xtandi, no Xofigo), there  was still an increased fracture rate, albeit lower. After 24 months of follow-up, they found:

• 33% had new fractures
• 1.3 fractures per patient with fractures
• Only 38% occurred at sites of metastases

This trial shows that all men taking hormone therapy for mCRPC are at high risk for fracture, but particularly if they use Xofigo, and if they previously used corticosteroids (e.g., with chemotherapy). The effect on bone continues after Xofigo is stopped. These are predominantly "fragility" fractures, not metastasis-related, and can be prevented with bone-strengthening agents like Xgeva or Zometa.

Second-line hormonal therapies

It has long been known that androgen deprivation therapy (ADT) sensitizes prostate cancer cells to radiation therapy. Could a more powerful type of hormonal therapy work even better?

The combination of Zytiga and Xofigo was tried in the ERA 223 trial. The trial was stopped early because there were about 3 times more fractures in the group receiving the combination than in the group receiving a placebo and Zytiga. The combination now carries a black-box warning against the combined use.

It appears that the problem may be at least partly resolved by using a bone-strengthening agent (like Xgeva or Zometa). When they looked at the subgroup who had taken bone-strengthening agents, 15% of those taking Xofigo+Zytiga vs 7% of those taking Zytiga-only experienced a fracture. So, even though Zometa or Xgeva reduced the fracture rates by about half in both arms, the fracture rate was still twice as high among those taking the combination. 

The combination of Xtandi and Xofigo is being tried in the EORTC1333/PEACE 3 trial. Because of the problems with the ERA 223 trial, they sent out a safety alert to assure that everyone in both arms was also getting a bone-strengthening agent. Bertrand Tombal (updated at 1 1/2 yrs) reported that skeletal events so far occurred in:

• 46% of men taking Xofigo and Xtandi without a bone-strengthening agent
• 3% of men taking Xofigo and Xtandi with a bone-strengthening agent
• 22% of men taking Xtandi without Xofigo and without a bone-strengthening agent
• 4% of men taking Xtandi without Xofigo and with a bone-strengthening agent

(update 9/14/24) Silke Gillessen presented the early results of PEACE3 at ESMO 2024. Compared to Xtandi alone, Xofigo+Xtandi:

• improved radiographic progression-free survival by 31%
• improved overall survival by 31%

Agarwal et al. reported on a small Phase 2 trial where 39 metastatic castration-resistant men were randomized to Xofigo+Xtandi or Xtandi alone. Bone metabolic markers were reduced significantly by the combination, suggesting increased efficacy. A safety analysis found few serious cytopenias and no skeletal events in either arm. A new post-hoc analysis found:

• PSA progression-free survival was 9 months for Xofigo+Xtandi vs 3 months for Xtandi-alone (not significantly different on this small sample size)
• Time to PSA progression after the next therapy was 19 months for Xofigo+Xtandi vs 8 months for Xtandi-alone (significantly different)
• Time to next therapy was 16 months for Xofigo+Xtandi vs 3 months .for Xtandi-alone (not significantly different)
• Overall Survival  was 31 months for Xofigo+Xtandi vs 21 months for Xtandi-alone (not significantly different)
• There were 3 asymptomatic fractures found in the Xofigo+Xtandi arm.

Presumably, the combination has a deleterious effect on the bone microenvironment or structural integrity. While Zometa has been proven to have no effect on survival as a monotherapy, in a subset of the STAMPEDE trial the combination of Zometa and Celebrex increased survival by 22%. Patients should not combine Xofigo with a second-line hormonal therapy without a bone-strengthening agent, and preferably only in a carefully watched clinical trial. Using them sequentially may be safer. Patients may wish to discuss adding Celebrex as well.

Clinical trials combining Xofigo with second-line hormonals include these:

• https://clinicaltrials.gov/ct2/show/NCT04237584
• https://clinicaltrials.gov/ct2/show/NCT02194842
• https://clinicaltrials.gov/ct2/show/NCT03344211
• https://clinicaltrials.gov/ct2/show/NCT03305224
• https://clinicaltrials.gov/ct2/show/NCT04597125
• https://clinicaltrials.gov/ct2/show/NCT05771896 (mHSPC)

Chemotherapy

Morris et al. reported the results of a small trial comparing Xofigo + docetaxel to docetaxel alone in 53 castration-resistant men who had ≥ 2 bone metastases. They were given either:

• Xofigo (55 KBq/kg) every 6 weeks for 5 injections and lower dose docetaxel (60 mg/m2) every 3 weeks for 10 infusions
• Standard dose docetaxel (75 mg/m2) every 3 weeks for up to 10 infusions
• The normal schedule for Xofigo is 55 KBq/kg once every 4 weeks for 6 injections
• The normal schedule for docetaxel is 75 mg/m2 once every 3 weeks for 6 infusions
• The timing adjustments were made for patient convenience
• Almost all had tried a second-line hormonal therapy
• Most were taking a bone-strengthening agent

With 52 weeks of follow-up:

• Median PSA progression occurred after 6.6 months in the combination arm vs 4.8 months in the docetaxel-only arm
• PSA declined by ≥ 50% in 61% of the combination arm vs 54% of the docetaxel-only arm
• Median radiographic or clinical progression occurred after 12 months for the combination vs 9 months for docetaxel only
• All 10 treatments were given for the combination, whereas there was a median of 9 of 10 treatments in the docetaxel-only arm
• 12% discontinued treatment in the combination arm vs 23% in the docetaxel-only arm
• Serious adverse events were suffered by 48% in the combination arm vs 62% in the docetaxel arm
• Serious blood disorders were noted more often for docetaxel-only

It seems that the more toxic docetaxel dose could be reduced by the combination without any loss of efficacy.

Xofigo was also found to work well after docetaxel. Docetaxel's effectiveness was not diminished by previous Xofigo.

These clinical trials combine docetaxel and Xofigo:

• https://clinicaltrials.gov/ct2/show/NCT03574571
• https://clinicaltrials.gov/ct2/show/NCT03737370

Immunotherapy

There is a synergy between radiation and immunotherapy (see this link). Radiation kills cancer cells and their proteins (antigens) are detected by immune cells that form antibodies to them. 

Marshall et al. reported the results of a small trial that randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. After median follow-up of 1.6 years:

• Median progression-free survival (PFS) was 39 weeks for the combination vs 12 weeks for Provenge alone.
• The % who had a PSA reduction by more than half was 31% for the combination vs 0% for Provenge alone
• Median overall survival was higher with the combination: not reached vs 2.6 years
• The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
• There were no increases in side effects for the combination

Increases in PFS and reductions in PSA and bone ALP are usually not seen for either medication alone, so it is noteworthy that the combination had an enhanced effect.

But immune stimulation will never be long-lasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one's own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These "checkpoint blockers" are currently represented by drugs that have been FDA-approved for use in other cancers, like Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor).  This trial did not find any clinical benefit in combining Xofigo and Tecentriq (atezolizumab) and the toxicity was high. A trial of the checkpoint inhibitor Keytruda+Xofigo also found no extra benefit to the combination. Hopefully, future Xofigo clinical trials will include a checkpoint blocker as well as an immune stimulant. There are two ongoing clinical trials at UCSF and in Melbourne of Lu-177-PSMA-617 combined with Keytruda. 

This clinical trial includes an arm where patients receive Xofigo + external beam radiation + Bavencio (avelumab):

• https://clinicaltrials.gov/ct2/show/NCT04071236

PARP inhibitors

PARP inhibitors (e.g., olaparib, rucaparib, etc.) have known activity in men who have certain DNA-repair defects, particularly BRCA mutations (either germline or somatic). They boost the deficiency in self-repair, causing the cancer cells to die. They may also be useful in conjunction with radiation. When radiation creates sublethal DNA damage, preventing the DNA-repair machinery from operating, a PARP inhibitor may put the cell over the edge.

van der Doolen et al. reported the results of an exploratory retrospective analysis of 93 castration-resistant patients at Johns Hopkins treated with Xofigo for bone metastases:

• 28 had DNA-repair defects (DRD+)
• 65 had no DNA-repair defects (DRD-)

Compared to the men who were DRD-, the DRD+ men had:

• Twice as high alkaline phosphatase (ALP) response: 80% vs 39%
• Longer time to ALP progression: 6.9 mos vs 5.8 mos. (not statistically significant)
• Longer time to next systemic therapy: 8.9 mos. vs 7.3 mos. (not statistically significant)
• Twice as long overall survival: 36.3 mos. vs 17.0 mos. 
• Better Xofigo completion rates: 79% vs 47%
• No difference in PSA response

Xofigo seems to work especially well in men who are DDR+. The combination of PARP inhibitors and Xofigo may be especially effective. A trial combining Xofigo with a PARP inhibitor (olaparib) and an immunotherapy (Keytruda) showed no more activity than a second second-generation hormonal, and the toxicity was a lot worse. 

There is a trial in Australia of a PARP inhibitor combined with Lu-177-PSMA-617.

These clinical trials examine the effect of DRD+ or PARP inhibitors on Xofigo effectiveness:

• https://clinicaltrials.gov/ct2/show/NCT04489719
• https://clinicaltrials.gov/ct2/show/NCT03076203
• https://clinicaltrials.gov/ct2/show/NCT03317392
• https://clinicaltrials.gov/ct2/show/NCT04071236

Earlier Treatment

A lab study at M.D. Anderson found that Xofigo was excellent at treating micro-metastases, but not as good at treating large bone metastases. This suggests that earlier Xofigo treatment may be preferable and that larger tumors are optimally treated with a combination medical therapy or with a combination with external beam radiation (see below).

In a retrospective study, survival after Xofigo treatment was associated with better performance status, lower PSA at the time of treatment, lower pain scores, less use of advanced hormonals, lower bone scan index, and normal ALP levels.

Hematologic toxicity and bone marrow failure are potential adverse events associated with using Xofigo after extensive bone metastases are already present (see this link and this one). A clinical study showed that high tumor burden predicted skeletal-related events (SREs) and lower overall survival.

Xofigo has only been tested in men with bone-metastatic CRPC, who have bone pain and no visceral metastases. It's use in earlier states of progression have been underexplored. This small study suggested there may be a benefit to Xofigo in some when bone metastases have been found post-prostatectomy, while they were still hormone sensitive. At least, it helped relieve bone pain.

This clinical trial compares (darolutamide +ADT) ± Xofigo in newly diagnosed (mHSPC) patients:

• https://clinicaltrials.gov/ct2/show/NCT05771896

This clinical trial includes Xofigo for biochemically recurrent patients before metastases are visible:

• https://clinicaltrials.gov/ct2/show/NCT04206319

External Beam Radiation

Because Xofigo is especially good at targeting micrometastaic bone metastases, and not so good at targeting the macroscopic bone metastases, it may be optimal to target the visible ones (if there are very few) with SBRT, and the invisible ones with Xofigo.

These clinical trials include Xofigo as well as SBRT to oligometastases:

• https://clinicaltrials.gov/ct2/show/NCT03361735
• https://clinicaltrials.gov/ct2/show/NCT03304418
• https://clinicaltrials.gov/ct2/show/NCT04037358

Radiosensitizers

There are several known radiosensitizers (medicines that increase the cell-killing potential of ionizing radiation). The problem with many radiosensitizers is that they may sensitize healthy cells too, increasing toxicity. Ideally, we want a medicine that only radiosensitizes cancer cells, while not affecting or even being radioprotective of healthy cells. Among the types of medicines being explored for this affect are PARP inhibitors and other DNA-damage repair inhibitors (above), heat shock protein inhibitors, HDAC inhibitors, idronoxil, and a plethora of natural products. Veyonda (idronoxil) has had some promising results when combined with Lu-177-PSMA-617 (see this link). So far, there are no clinical trials pairing radiosensitizers with Xofigo.

Retreatment

While there was no benefit found in increasing the dose per treatment over 55 KBq/kg or extending the number of consecutive treatments beyond 6 (see this link), repeat treatment may be beneficial. Sartor et al. found that repeat cycles are effective and well-tolerated. Multiple treatments are commonly used for Lu-177-PSMA-617.

 BAT

The RESTORE - Cohort C trial of bipolar androgen therapy (BAT) found that testosterone-loading among men who had not had Xtandi or Zytiga only had a benefit among men with lymph node-only metastases. This raises the possibility that Xofigo may be complementary to BAT in men with both lymph node and bone metastases.

This clinical trial will combine Xofigo and BAT in mCRPC patients:

• https://clinicaltrials.gov/ct2/show/NCT04704505

Th-227-PSMA-antibody

Th-227 decays into Ra-223. While Th-227 readily chelates to the PSMA ligand, Ra-223 does not. So it is possible that as it decays, the Ra-223 detaches and may be picked up by bone tissue, just as Xofigo does. If so, there may be a double treatment effect.

This clinical trial uses Th-227-PSMA-antibody:

• https://clinicaltrials.gov/ct2/show/NCT03724747

For those trying to decide between Lu-177-PSMA and Xofigo, here's a comparison (but not a randomized comparative trial) about the way the two radiopharmaceuticals work.

Use Pluvicto after or together with?

The VISION trial of Pluvicto (Lu177PSMA617) excluded patients that had been previously treated with Xofigo. Therefore, the current FDA approved indication for Pluvicto precludes men who had been previously treated with Xofigo. Ra223 is much better at killing prostate cancer in bone, because it is a more powerful alpha-emitter. Pluvicto kills PSMA-avid cancer in all tissues, so it can "clean up" much of what Xofigo leaves behind. In a small trial, Sartor et al. and Rahbar et al. tried Pluvicto after 6 infusions of Xofigo. They found that the toxicity was reasonable -- blood adverse events in about a third, almost all of whom also received docetaxel. It bears further investigation.

Here's a trial in Melbourne combining both:

https://clinicaltrials.gov/ct2/show/NCT05383079

Avoiding radiation damage to salivary glands with Ac-225-PSMA-617 therapy

As we await the results of the VISION trial of Lu-177-PSMA-617, research continues into improving radiopharmeuticals. Ac-177-PSMA-617, which is more lethal to cancer cells within a more limited distance, is one of several promising alternatives (see this link).

One of the serious side effects of the experimental Ac-225-PSMA-617 therapy is radiation damage to salivary glands. "Xerostomia" (dry mouth) also occurs with Lu-177-PSMA-617 therapy, but it is usually transient and less severe, although it does increase with the number of treatments. Sathkegke et al. reported occurrence in 85% of South African patients treated with Ac-225-PSMA-617, but no one stopped treatment entirely because of it. Kratchowil et al. reported occurrence of xerostomia in Heidelberg, Germany so severe in 4 of 40 treated patients that treatment had to be discontinued. Feuerrecker at al reported that all their treated German patients suffered from xerostomia; it was so severe as to curtail treatment in 6 of 26 patients.

Acute, low-grade xerostomia is caused by the temporary irritative inflammatory effects of the radiopharmaceutical on salivary tissue. Lasting damage may result from radioablation of the saliva-producing cells and the nerves that innervate them, and their replacement with and obstruction of the ducts with mucus and scar tissue. Loss of saliva can make chewing and swallowing almost impossible, leading to choking and vomiting. Digestion is impaired, and the ability to taste food may be lost. Saliva has antimicrobial properties, so its loss can lead to tooth decay, gum disease, and oral thrush. Speaking can become difficult.  It can feel like burning, and interfere with sleep. Humans normally produce about a liter of saliva each day.

Some simple therapies (local cooling with ice, Vitamin C, lemon juice, and PMPA) have been found to be ineffective. Taïeb et al. report that treatment with botulinum toxin, Vitamin E and MnBuOE may be more successful, but that regeneration of salivary glands with stem cells or genetic modification may ultimately be necessary. Riley et al. found very low quality of evidence that amifostine, pilocarpine, palifermin, biperidine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin) may be useful. Nail et al. found sublingual atropine reduced salivary uptake in mice. More benefit may be accomplished with some of the following strategies:

Sialendoscopy

Rathke et al. reported the successful use of sialendoscopy in 11 patients. Sialendoscopy is a kind of endoscopic procedure involving the insertion of a thin probe into the salivary glands. It dilates the openings that have closed due to inflammation. They irrigated the glands with saline and prednisolone. It only worked when done immediately.

Pre-treatment with PSMA-11

PSMA-11 is the small molecule ligand used with Ga-68-PSMA-11. Taken without the radiotracer, it attaches to the salivary tissue, where it can block further uptake by the PSMA-617 ligand. Kalidindi et al. found that in mice, pretreatment with 1000 picomoles blocked uptake of Lu-177-PSMA-617 in the salivary glands and kidneys; but uptake, while reduced, was still at therapeutic levels in tumor tissue. This finding would have to be replicated in clinical trials.

Use only when there is significant PSMA-avidity

Damage to normal, healthy tissue increases when there is insufficient PSMA-avid tumor tissue to attach to. Gaertner et al. found that across 135 patients, uptake by normal tissues of the salivary glands, tear ducts, kidneys, and other vital organs was significantly reduced in men with high tumor load. Gafita et al. and Burgard et al. confirmed this "tumor sink" effect. While it is true for many pharmaceuticals that earlier use is more effective and less toxic, there is a balance to be struck between the tumor-killing effect and toxicity for the PSMA-targeted radiopharmaceuticals. We have seen that such treatment can be too late as well, when new metastases lose PSMA-avidity (see this link). It may be a good idea to reduce dose for low tumor volume.

Mix Lu-177-PSMA-617 and Ac-225-PSMA-617

A cocktail of the two may increase the cancer-killing power of Lu-177-PSMA-617 while decreasing the toxicity of Ac-225-PSMA-617. Khreish et al. reported that only 5 of 20 patients given the cocktail reported mild xerostomia.

Use a PSMA antibody

PSMA-617 and PSMA-11 are small molecules that have been found to attach to the PSMA molecule on the surface of prostate cancer cells. They are not as specific as other ligands. Scott Tagawa is exploring the use of a PSMA antibody, called J591 in two clinical trials (this one and this one), that may be more specific than the small molecules. In a previous clinical trial, there were no reports of xerostomia.  The clinical trial of Th-227 targeting PSMA uses a highly specific antibody.

Use a non-PSMA-targeted ligand

Another strategy is to forgo the PSMA target entirely. Ac-225 has been attached to an antibody that very specifically targets hK2 (one of the 4 prostate cancer proteins detected by the 4KScore test). It has entered a clinical trial.

Beware of MSG and other supplements

Harsini et al. conducted a small clinical trial where patients were randomized to take tomato juice with and without monosodium glutamate (MSG). Glutamate is a known heavy-metal chelator. Each patient had two double-blinded PSMA PET scans -- one with MSG; the other without MSG. MSG did reduce the uptake of PSMA into the salivary glands and the kidneys. Unfortunately, it also blocked the uptake of PSMA into tumor tissue. Armstrong et al. reported a similar trial where patients could swish MSG in their mouths or ingest it. Each patient had Ga-68-PSMA-11 PET scans with and without MSG. Swishing had no effect. Oral ingestion reduced uptake in salivary glands and in tumors. Patients getting PSMA theranostics should avoid MSG and Chinese food.

Because the PSMA-targeted radiopharmaceuticals are very loosely held together (chelated) by a coordination complex, it is easily reversed by other heavy metals (like iron, cobalt, vanadium, etc. supplements) or other chelates or chelators (like those frequently found in multi-mineral tablets). Curcumin, a popular supplement, has been found to be a chelator. Use of such supplements may increase the toxicity of these radiopharmaceuticals, or render them ineffective. Antioxidants and free radical absorbers may interfere with the DNA damage that radiopharmaceuticals are trying to achieve. To be safe, and to maximize their effectiveness, patients should avoid all supplements during therapy.

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

Two technologies have come together to allow for a new kind of radiation treatment known as simultaneous integrated boost (SIB), or, more informally, “dose painting.” The two technologies are: 

1. improved imaging by multiparametric MRIs that can more precisely locate tumors within the prostate, and 
2. improved external beam technology that can deliver doses with submillimeter accuracy. 

Dose painting can be achieved with brachytherapy as well. But just because it can be done, doesn’t mean it should be done. That is, the following two questions must be answered:

1. Is there any benefit in terms of oncological outcomes?
2. Is there any increase in treatment toxicity attributable to it?

The arguments for dose painting include:

• There is often a dominant intraprostatic lesion (DIL) or index tumor. There is some evidence that cancer spreads via clones from it. Because such tumors are often large and high grade, some think that the index tumor may be relatively radioresistant, perhaps because of hypoxia or cancer stem cells. Therefore, a higher dose of radiation may be necessary to kill its cancer cells.
• By concentrating the radiation’s killing power at the DIL, it may be possible to reduce the radiation dose where it is less needed, and thus spare organs at risk (e.g., bladder and rectum).

The arguments against dose painting include:

• The index tumor hypothesis is far from proven. In fact, prostate cancer is multifocal in about 80% of men. Reducing the dose elsewhere is risky because cancer cells may survive and propagate.
• If the dose needed to kill the cancer cells is inadequate, why not increase the dose throughout the prostate to a dose that is adequate? With today’s pinpoint technology, the clinical target volume (the prostate) can be defined with sub-millimeter accuracy and near-perfect shaping.
• Using mpMRI to precisely delineate the DIL may miss much of it. In fact, a study at UCLA found that tumors delineated by mpMRI missed 80% of the tumor's actual volume.
• While mpMRI is good at finding large high-grade tumors, sometimes the highest grade tumor is not large, and mpMRI cannot locate it.
• Intense foci of radiation may increase the probability of normal tissue complications, including damage to the urethra, bladder neck, sphincter, rectum and bowel.

With all these pros and cons in mind, the FLAME randomized clinical trial was instituted to determine whether dose painting is effective and safe in real-world application. Kerkmeijer et al. reported the results of 571 patients treated at 4 institutions in Belgium and the Netherlands from 2009 to 2015. Patients were:

• Predominantly (85%) high risk
• Adjuvant ADT was given to 65% for a median of 18 months.
• Received hypofractionated radiation to the prostate: 77 Gy in 35 treatments, which is biologically equivalent to 82 Gy in 41 treatments.
• Half received a SIB to the DIL as well: 95 Gy in 35 treatments, which is biologically equivalent to 116 Gy in 58 treatments.
• The boost dose was reduced sometimes to meet very tight dose constraints on organs at risk.

After 6 years of follow-up:

• 5-year biochemical disease-free survival (bDFS) was 92% for those that received the SIB and 85% for those who didn't, a significant difference.
• Both biochemical failures and clinical recurrences were cut in half by the SIB
• In the limited follow-up period, there weren't enough distant metastases or deaths to detect a significant difference.
• There were no significant differences in Grade 2 or Grade 3 urinary or rectal  toxicity,
• As previously reported, late-term Grade 2 or greater toxicity was 10% for rectal, 27% for urinary with no significant differences.
• There was no late-term Grade 3 rectal toxicity, and minimal late-term Grade 3 urinary toxicity in either arm.
• There were no significant differences in patient-reported quality of life for urinary, rectal or sexual outcomes.

Because oncological results were as good as brachy boost therapy, the current gold standard for treating high-risk patients, and late-term urinary toxicity was minimal, hypofractionated IMRT with SIB is poised to become the new standard of care for high-risk patients. Longer follow-up will determine whether the results hold up.

(update 9/21/22) Tree et al. reported the results of the DELINEATE trial in 256 men treated at Royal Marsden in the UK. Patients had intermediate (43%) or high-risk (57%) PCa. All had DILs detected via MRI. All received ADT. They were randomized to one of 3 cohorts:

1. 74 Gy in 37 treatments to prostate+seminal vesicles + 82 Gy SIB to DIL
2. 60 Gy in  20 treatments to prostate+seminal vesicles + 67 Gy SIB to DIL
3. (high-risk only)same as Cohort A + 60 Gy to pelvic lymph nodes

After more than 5 years of follow-up:

• Gastrointestinal toxicity grade 2 or more: 13% Cohort A, 15% Cohort B, 21% Cohort C
• Urinary toxicity grade 2 or more: 13% Cohort A, 18% Cohort B, 18% Cohort C
• Freedom from biochemical failure: 98% Cohort A, 97% Cohort B, 95% Cohort C

Excellent results from SIB to DIL, even in high-risk patients. Moderate toxicity.

There are some opportunities for improving results for patients even further.

• SBRT with SIB: As we've seen extreme hypofractionation may provide more lasting results with equally good toxicity. Whole gland treatment with as high as 47.5 Gy in 5 fractions did not incur any excess toxicity in trials (see this link). 
• Tumor detection and delineation with PSMA PET/CT scan: a small comparative study showed that PSMA PET/CT had superior sensitivity and positive predictive value compared to mpMRI. More importantly, it can eliminate patients who would not benefit from localized treatment because of occult metastases.
• Genomics to detect radio-resistant tumors and radiation sensitivity
• Imaging to detect hypoxic tumors (e.g., BOLD MRI, FAZA PET, or MISO PET)

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

• They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
• 72% received adjuvant ADT for a median of 9 months
• 19% received elective nodal radiation

After a median follow-up of 49.5 months:

• 4-year biochemical recurrence-free survival  (bRFS)was 82%
• Higher dose, longer ADT, and nodal radiation were associated with better bRFS
• 4-year metastasis-free survival was 89%
• Late grade 3 GU toxicity was 2.3%
• Late grade 3 GI toxicity was 0.9%
• Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.

	Follow-up	bRFS	BED	ADT (median)	Late GU Toxicity Grade ≥3
SBRT (1)	4 yrs	82%	198-253 Gy	9 mos.	2.3%
Surgery+SRT (2)	5 yrs	78%	154 Gy	6 mos.	8% (3)
HDR-BT (4)	5 yrs	91%	227-252 Gy	6.3 mos.	3-16%
LDR- Brachy Boost (5)	5 yrs	86%	227 Gy	12 mos.	19%
HDR-Brachy Boost (6)	6 yrs	88%	267 Gy	12 mos.	2.5%
IMRT (7)	5 yrs	88%	174 Gy	28 mos.	2.5%

SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments

bRFS= biochemical (PSA) recurrence-free survival

BED= biologically effective dose (comparable effectiveness)

ADT= androgen deprivation therapy used for a limited time to improve outcomes

late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy

HDR-BT = high dose rate brachytherapy (temporary implants)

LDR-BT = low dose rate brachytherapy (permanent implants/seeds)

Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 

IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(1) https://www.redjournal.org/article/S0360-3016(21)00068-7/pdf

(2) https://riskcalc.org/ProstateCancerAfterRadicalProstatectomyNew/ with GS 8

(3) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext

(4) https://www.redjournal.org/article/S0360-3016(11)00552-9/abstract

(5) https://www.redjournal.org/article/S0360-3016(16)33484-8/abstract

(6) https://www.thegreenjournal.com/article/S0167-8140(18)30238-X/fulltext

(7) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).