Showing posts with label nuclear medicine. Show all posts
Showing posts with label nuclear medicine. Show all posts

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




Tuesday, June 6, 2017

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone  (updated here) (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.62

An unplanned secondary analysis presented at ESMO 2018 and published in European Urology looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

In an 5-year update, there was no difference in mortality depending on whether the patient had many or few metastases:

The hazard ratios for men with high burden patients only were:
STAMPEDE: 0.54

The hazard ratios for men with low burden patients only were:
STAMPEDE: 0.55

Early use of Zytiga+Docetaxel

Overall survival is only available for men with high volume of metastases, but radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). 

For men with high volume of metastases, median overall survival increased from 42 months with docetaxel only to 61 months with docetaxel+Zytiga.



Early use of darolutamide (Nubeqa) + Docetaxel

In the ARASENS trial, the "triplet" of ADT+ docetaxel + darolutamide reduced mortality by 32% over ADT+docetaxel (HR= 0.68).



Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The early use of Zometa is frowned upon because side effects increase over time. However, if an older man already has osteoporosis, Zometa+Celebrex is a good combination. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43-month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel. However, the use of Zometa when one is still hormone-sensitive is controversial. An argument can be made for putting it off until there is evidence of osteoporosis on a DEXA scan - the risk of the worst side effect- osteonecrosis of the jaw - increases with the amount of time taking it.

The hormonal therapies have different modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. (Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial and STAMPEDE found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting, but side effects were worse. 

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

Based on patient-rated global quality of life after 2 years (see this link), docetaxel and abiraterone were not meaningfully different in patients randomized to one or the other. Abiraterone was better than docetaxel at 12 weeks and 24 weeks. One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

The PEACE-1 trial showed that the combination of docetaxel and Zytiga improved outcomes significantly.

A major clinical trial, ACIS, found that the combination of Erleada and Zytiga increased radiographic progression-free survival in men who were already castration-resistant. That combination improved results (in the AASUR trial) when given as an adjuvant therapy along with prostate radiation to men with very high-risk localized prostate cancer, and will be testedamong high-risk patients with high Decipher scores in the PREDICT-RT trial. The combination is being tried along with salvage radiation in men who have failed prostatectomy in the INNOVATE trial. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The PSMAddition trial is for men who are newly diagnosed or metastatic with metastases. The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival was reached at the extended follow-up of the STAMPEDE trial. Median survival was 46 months in the SOC group, and 79 months in the Zytiga group. So, early Zytiga increased median survival by 33 months; In LATITUDE (in which all patients were more progressed), early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These trials are still active:





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)

Sunday, December 18, 2016

Small Cell Prostate Cancer Clinical Trials

(frequently updated)

Small Cell Prostate Cancer (SCPC), and more generally Neuroendocrine Prostate Cancer (NEPC), are thankfully rare types of prostate cancers. They are not responsive to hormone therapy, to taxanes (Taxotere or Jevtana), or to radiation. They are difficult to detect and monitor with the kinds of imaging used to detect prostate adenocarcinoma (mpMRI, bone scans, PSMA PET scans), but may show up with FDG PET (see this link). They do not put out PSA, PAP or bone alkaline phosphatase. Special biochemical tests or biopsies for chromogranin A, neuron-specific enolase (NSE), synaptophysin,  DLL-3, CD56, and other biomarkers are required. It often appears at a "mixed type." 

Sub-types

Not all neuroendocrine prostate cancers carry the same prognosis. Aggarwal identified a sub-type that became prevalent in 17% of patients who were heavily pretreated with enzalutamide (Xtandi) and abiraterone (Zytiga). He calls this "treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC). The pre-treatment probably selected for this subtype that may be partially responsive to familiar therapies. The "treatment-emergent" subtype and the small amounts sometimes detected initial biopsies do not appear to be as virulent (see this link). There are some studies that indicate that they may appear spontaneously in later stages of normal prostate cancer development. Aggarwal commented:
“Although long term androgen deprivation therapy may be associated with the development of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in a minority of patients, multiple studies have confirmed the long-term benefit of abiraterone and enzalutamide for prostate cancer patients in various disease settings. Use of these agents should not be limited by concern for the subsequent development of t-SCNC.”
Aggarwal has announced a clinical trial where he will be testing a combination of Xtandi, Keytruda, and ZEN-3694 in (among others) a group of men identified with the t-SCNC subtype. ZEN-3694 is an experimental medicine that inhibits a gene called MYC, which is often over-expressed in advanced prostate cancer. 

Aggarwal is also testing FOR-46 targeting the CD-46 protein that often is expressed in neuroendocrine tumors.

Chemotherapy

Because of the "mixed type," chemo often includes a taxane. More often, a platin is mixed in a cocktail with another chemo agent, like etoposide. A couple of case reports from Japan (see this link and this one) reported some success with a platin combined with irinotecan.

This clinical trial at Duke has two chemotherapies (cabazitaxel and carboplatin), as well as two checkpoint blockade-type immunotherapies (nivolumab and ipilimumab):
CHAMP

Nuclear Medicine/ Somatostatin

The Urology Cancer Center in Omaha, Nebraska has announced a clinical trial of 225Ac-FPI-2059 for neuroendocrine cancers. FPI-2059 is a small molecule that attaches to the neurotensin receptor 1 peptide that is expressed by neuroendocrine cancer cells.

Another radiopharmaceutical has been tried by the nuclear medicine department at the University of Heidelberg. I suggest that anyone who is interested email or call (they all speak English) Uwe_Haberkorn@med.uni-heidelberg.de Phone: 06221/56 7731. With the euro now at close to parity with the dollar, this medical tourism is an especially attractive option:

213Bi-DOTATOC shows efficacy in targeting neuroendocrine tumors

A similar radiopharmaceutical using Lu-177-DOTATATE (called Lutathera) has been FDA-approved for small cell cancer affecting the digestive tract. DOTATOC (and also DOTATEC and DOTATATE) binds to somatostatin receptors on the small cell digestive tract cancer surface, where it is highly expressed. It is rarely expressed in small-cell prostate cancer, but there have been some isolated case reports like this one or small trials like this one. This means that treatment with a somatostatin analog (octreotide, lanreotide, or pasireotide) may be somewhat effective even without the radioactive emitter attached to it. These drugs are available now in the US, are not toxic, and your doctor can prescribe them without a clinical trial. there is a clinical trial of it in London for any solid tumor:

https://clinicaltrials.gov/ct2/show/NCT02236910

These clinical trials include somatostatins:

https://clinicaltrials.gov/ct2/show/NCT01794793
https://clinicaltrials.gov/ct2/show/NCT02754297

This clinical trial at Johns Hopkins uses Lutathera to treat neuroendocrine prostate cancer, specifically:


While the presence of somatostatin receptors in the tumor can be determined by pathological analysis (immunohistochemical (IHC) staining for SSTR2), there is an FDA-approved PET scan that uses Ga-68-DOTATATE that can detect it without a biopsy. It is used to detect neuroendocrine tumors that are often non-prostatic. Researchers at Emory found that Ga-68-DOTATATE uptake is higher even in neuroendocrine tumors of prostatic origin, which suggests that somatostatin-based therapy may be beneficial. (One patient who was positive for a BRCA2 mutation but negative for NEPC had high uptake as well.)

DLL3

DLL3 is a protein that is expressed on the surface of neuroendocrine cells regardless of the cancer of origin, and has been identified in two-thirds of neuroendocrine prostate cancer (NEPC) cells. An antibody linked to a chemotherapy, called Rova-T, against DLL3 has been developed and has shown some promise against NEPC in a preclinical study. Unfortunately, AbbVie discontinued R&D after it failed to meet goals for small cell lung cancer (SCLC). A Phase 2 trial that included NEPC was discontinued. Misha Beltran at Dana Farber has tried an antibody-drug conjugate (rovalpituzumab teserine) targeted to DLL3 on a single patient. After two treatments, his metastases shrank and stabilized.

Harpoon has announced a clinical trial of HPN328  for people with advanced cancers that express DLL3. HPN328 is a bispecific T-cell engager (BiTE) that targets DLL3 and also promotes T cells to attack those cells exhibiting it. AMG757 is also a BiTE. Amgen has announced a clinical trial of AMG 757 for advanced prostate cancer. Phanes Therapeutics has a BiTE clinical trial targeting DLL3.

AMG119 is a CAR-T therapy that targets DLL-3. CAR-T involves treating one's own T-cells by sensitizing them to DLL3. Both of these create a T-cell and a cytokine response in environments that otherwise have low immune cell activity. That response may kill bystander cells, and through a phenomenon called "antigen spreading," may be able to kill other cancer cells that do not exhibit DLL3. (BiTE and CAR-T therapies that target PSMA are  in clinical trials noted at end of this article)

The Wang Lab at Duke has specific expertise in morphological analysis of NEPC and IHC staining for DLL3. It may be a good idea to get a second opinion from them.

Checkpoint blockade

Another recent discovery is that PD-L1 is highly expressed in SCPC. This opens the door to immunotherapies that target the PD-1/PD-L1 pathway, like Keytruda.

PD-L1 expression in small cell neuroendocrine carcinomas

Small clinical trials have so far shown little benefit: