Newest radiopharmaceutical: Th-227-PSMA-antibody

Bayer has announced a new clinical trial of the latest entry in the race for radiopharmaceuticals to treat prostate cancer, joining Lu-177-PSMA-617, Ac-225-PSMA-617, and I-131-MIP-1095. They are trying Thorium-227 attached to a PSMA antibody.

Thorium-227, like Ac-225, is an alpha-particle emitter. Alpha emitters are very powerful, but very short range, only killing cells that are 2 to 10 cells away from the cancer cell it attaches to. This may limit its toxicity, but may require higher doses for larger, more widespread tumors.  Beta emitters, like Lu-177, are less powerful, but the beta particle penetrates to a much greater depth, affecting about 125 cells. Researchers at the University of Heidelberg are experimenting with mixtures of the two.

The other part of the equation is the ligand that the radioactive atom is attached to and that attaches to the PSMA protein on the prostate cancer cell. Ligands include PSMA-617, PSMA-I&T, MIP-1095, and J591. Ligands may be small molecules, antibodies, or "minibodies." Bayer is using a proprietary antibody-type ligand that they developed for the purpose. Ligands that are more specific for PSMA have less toxicity.

On the other side of the ligand molecule, it must bind very tightly to the radioactive element. If it doesn't, the radioactive element might be released into systemic circulation where it can damage healthy cells. Heavy metals, like thorium, are attached relatively weakly by a process called "chelation," but some chelators are stronger than others. Researchers have so far been unsuccessful in developing a stable chelate for Ra-223 (the main ingredient in Xofigo, which is also manufactured by Bayer) to a PSMA ligand. However, Th-227 decays into Ra-223, so it is unknown if the thorium chelate will continue to hold as it decays. However, Bayer has already begun two clinical trials for Th-227 chelated to an antibody for non-Hodgkin's lymphoma since 2015, and for ovarian cancer and mesothelioma since April, which have not been terminated for excess toxicity. There is every reason to hope that the chelation complex they devised for the PSMA-antibody ligand holds up in biological systems. But if it doesn't hold chemically, it becomes the active ingredient in Xofigo, and may be doubly therapeutic in men with bone metastases.

This is a dose-finding (Phase 1) clinical trial among 108 patients with metastatic castration-resistant prostate cancer. They list 4 locations that will be recruiting: Memorial Sloan Kettering in NYC, Tulane (New Orleans), as well as locations in the UK and Finland.

I-131-MIP-1095 has entered a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here. (Update 4/2020) The clinical trial has begun recruiting in 17 locations in the US and Canada.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

175 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

Another radiopharmaceutical in clinical trials is Lu-177-PSMA-617 .  There are various phase 1 and 2 clinical trials in the US and internationally (see list at the end of this link).

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.

For information on the trial of Th-227-PSMA, see this link.

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.

177Lu Basket Trial (begins June 18, 2024)

Because there are several subtypes of neuroendocrine PCa, Novartis is running a trial that takes patients with 3 different subtypes and treats them with a radiopharmaceutical with the most appropriate ligand tailored to the dominant subtype. A biopsy determines whether it is neuroendocrine and which of 3 subtypes predominates. 177Lu is attached to any of the following 3 ligands:

1. PSMA
2. SSTR2 (Somatostatin receptor)
3. GRPR (Gonadotropin releasing hormone receptor)

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:

https://clinicaltrials.gov/ct2/show/NCT05691465

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:

Avelumab (Duke)

Pembrolizumab (UCLA)

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.

See discussion of early results of PEACE1.

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).

See: discussion of triplet therapy

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:

• apalutamide + Zytiga + debulking (RP or RT). (first results expected Feb 2024)
• Johns Hopkins is testing a PARP inhibitor for potential use instead of ADT in men with germline DNA repair defects(first results expected Dec 2023)
• enzalutamide ± Keytruda  (first results expected in  July 2026)

Timing is everything with docetaxel (and hormone therapy and probably with immunotherapy and radiopharmaceuticals too)

The conventional wisdom with cancer is that "earlier is better." As cancers progress, they mutate: there are many more genetic errors in older cancers than in younger ones (see this link). Because of this, a therapy that may work well against a cancer in one stage of its development, may not work at all in an earlier or a later stage.

Prostate cancer is one of the most slow-growing of cancers in its early stages. This is why we can take so much time to decide on initial treatment, even in high-risk cases (see this link). It is also why low-risk men may safely choose active surveillance over immediate radical therapy. Progression is only weakly correlated with time since diagnosis, even for recurrences (see this link).

Early Use of Docetaxel

We have already seen that docetaxel is of limited (if any) use when combined with radiation therapy and ADT for high-risk cancer patients (see this link). It is also ineffective when combined with prostatectomy and ADT for high-risk cancer patients (see this link). However, it can improve prognosis in men who have low PSA (<0.4ng/ml), high Gleason grade (8-10), and good performance status (see this link).

Oudard et al. conducted a randomized clinical trial of docetaxel+ADT vs ADT-alone in non-metastatic men with a recurrence after primary treatment. All 250 patients were "high risk," which was defined as at least one of the following:

• Gleason score ≥ 8
• PSA velocity > 0.75 ng/ml/year
• PSADT ≤ 6 months
• time to recurrence ≤ 12 months

Previous treatments were:

• 73% had prior prostatectomy
• 27% had prior primary radiotherapy ± ADT
• 60% of men who had a prostatectomy also had salvage EBRT

The outcomes were as follows:

• Median PSA progression-free survival was no different:19 months if they got docetaxel, 20 months if they didn't
• Median time to radiographic progression was no different: 9 years in each group
• There was no difference in 12-year overall survival rates: 60% in the docetaxel group, 55% in the no-docetaxel group. (The docetaxel group was 2 years younger)
• Adverse hematological events from docetaxel included neutropenia (48%), febrile neutropenia (8%) and thrombocytopenia (3%)

CHAARTED showed that the survival increase attributable to docetaxel in recently-diagnosed, metastatic men was only observed among men with a high volume of metastases, but not among men with a low volume of metastases. "High volume" was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae. 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.

One small observational study suggested that docetaxel may benefit men who are castration-resistant but are not yet detectably metastatic. At the other end of the progression spectrum, in men who are both metastatic and castration-resistant, docetaxel added 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.

The "sweet spot" for docetaxel seems to be after there are detectable metastases but before castration resistance is fully established. Used earlier, it seems to have no effect in most men; used later, it is still effective, but less so.

Early Use of Docetaxel + Second Line Hormonal Therapy

Triplet therapy means combining docetaxel with a second-generation hormonal medication and ADT. Triplets with abiraterone, darolutamide, and enzalutamide have been found to confer greater benefit than docetaxel+ADT in newly-diagnosed metastatic men (discussed here). The benefit held with darolutamide (in the ARASENS trial) even in men with low metastatic burden. Presumably, there will be a similar benefit with abiraterone when the PEACE1 trial matures.

Docetaxel remains effective even after second-line hormonals (e.g., Zytiga, Xtandi) have stopped working. In fact, there have been cases where use of docetaxel has reversed resistance to them caused by the AR-V7 splice variant. However, when men are already castration-resistant, combining docetaxel and Xtandi slowed progression but did not result in a survival advantage over docetaxel alone in the Phase II CHEIRON trial. The Phase III PRESIDE trial proved that docetaxel could reverse Xtandi resistance, but did not increase survival.

Again, earlier use of docetaxel is better.

Early Use of Hormone Therapy

It is well established that hormone therapy alone adds nothing to the survival of localized prostate cancer (see this link and this one). We also know that hormone therapy adds nothing to the effectiveness of radiation therapy for favorable risk prostate cancer (see this link and this one and this one). Even with recurrent prostate cancer post-prostatectomy, a major randomized clinical trial (RTOG 9601)  found that adding long-term antiandrogen therapy to radiation did not increase outcomes as much in men who had Gleason score ≤ 7, PSA ≤ 0.7 ng/ml or negative surgical margins.

Men who started on ADT earlier developed castration resistance significantly later. This effect was also noted in the TROG 03.04 RADAR trial. The authors wrote, "The cumulative incidence of transition to castration resistance was significantly lower in men receiving [longer term ADT with their EBRT]."


Early Use of Second-line Hormone Therapy

We have learned that the use of abiraterone (Zytiga) in newly-diagnosed metastatic men increases survival markedly over waiting. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). In the STAMPEDE trial, median (50%) survival was 76.6 months with Zytiga vs 45.7 months with ADT alone.  So, early Zytiga increased median survival by 31 months, reducing mortality by 38%; In LATITUDE, early Zytiga increased median survival by16.8 months. Abiraterone was equally effective regardless of the number of metastases or whether they were classified as higher or lower risk (see this link).

Enzalutamide (Xtandi) is probably also beneficial if used earlier. A non-randomized clinical trial of early use of Xtandi showed it is very effective if used earlier (see this link), and a Phase 3 trial for its use in hormone-sensitive prostate cancer has had good results, according to a press release.

The FDA has approved apalutamide (Erleada) and enzalutamide (Xtandi) for use in non-metastatic castration-resistant prostate cancer. Darolutamide and abiraterone (Zytiga) will probably also be approved for this indication. Non-metastatic castration-resistant prostate cancer is probably an early version of metastatic castration-resistant prostate cancer, where micrometastases have not yet grown large enough to become detectable on a bone scan/CT.

Clinical trials suggest or are in process to determine if there is a role for advanced hormonal agents even earlier; for example in any of the following early settings:

• as part of an active surveillance protocol for men with favorable risk prostate cancer (see this link)
• adjuvant to radiation in high-risk localized prostate cancer (see this link)
• when it as advanced to only as far as pelvic lymph nodes (Stage N1 M0) (see this link)
• when it is recurrent but not yet detectably metastatic (see this link)

Early Use of Immunotherapy

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 in one small study (see this link). There are several clinical trials to help determine whether immunotherapy can play a role in extending the time that a man can stay on active surveillance (see this link and this one and this one).

In the "CHECKMATE 650" clinical trial of a combination of the two checkpoint inhibitor-type immunotherapies, nivolumab (Opdivo) and ipilimumab (Yervoy), there was some response (in 25% of pre-chemo men and 10% of post-chemo men) from the combination, but no response from either drug alone in earlier trials. However, all of the responders  (60% of the pre-chemo group and 40% of the post-chemo group) had a high mutational burden and/or showed the presence of PD-L1 in the tumors (33% of the pre-chemo group and 19% of the post-chemo group). Conversely, none of the men who had low mutational burden or PD-L1 had any response to the combination therapy. Toxicity was unacceptably high. This indicates that the cancer must evolve to a high degree of genetic breakdown before such therapies become effective. Early use causes unacceptable toxicity without any survival benefit.

At some point, cancer cells start displaying antigens that can be recognized by the immune system as "non-self," but it is not clear when that occurs in prostate cancer progression. Perhaps the fragments generated radiation may make the cancer more susceptible to immune attack (see this link). However, chemo, which also generates antigen fragments, has failed to stimulate an immunotherapy response from checkpoint inhibitors. The combination of docetaxel with a checkpoint inhibitor has proven to be ineffective in this trial and this one. It is also unclear when immune infiltration into tumors can occur, when checkpoint inhibitors (like PD-L1) begin to appear, and when regulatory T cells are overwhelmed by killer T-cells. Pro- and anti-inflammatory cytokines undoubtedly play a role in immune signaling and may occur at different stages.

Early Use of Radiopharmaceuticals

The ideal candidate for Xofigo will get all 6 treatments, preferably earlier, while bone health is still good (see this link). It has been found to work better on smaller tumors, so it is best used earlier rather than later (see this link). Because the combination of Xofigo and Zytiga caused excessive fractures and deaths (see this link), they can't be given simultaneously, at least not without a bone-preserving agent (like Zometa or Xgeva). Since a full cycle is completed in 24 weeks, taking Xofigo before Zytiga allows one to get the benefit of both in less time.

We do not know enough about the natural history of PSMA yet. We don't know when the PSMA protein first appears on the tumor surface. It has been detected in "high risk" patients, and is more often associated with higher grade cancer and in men with higher PSAs (see this link and this one). It as been detected in up to 95% of metastases. PSMA-based PET scans (Ga-68-PSMA-11 or DCFPyL) are used to check for PSMA-avidity before treatment. Without significant PSMA, the radiopharmaceutical would have nothing to latch onto, and might cause toxicity with no cancer-killing benefit. This is called the "tumor sink effect" and was noted in this study and this one.

A pilot test in South Africa suggests that Ac-225-PSMA-617 had good efficacy in patients who were not heavily pretreated, but their cancer was more progressed when treated. A trial with Lu-177-PSMA found that overall survival was 11 months in patients who had already had chemo (and were more progressed) and was 27 months in chemo-naive patients (who were also less progressed). Earlier seems to be better.


Although it is generally true that earlier treatment is better, we have learned that there are exceptions. There is tremendous individual variation, and it is likely that the window of opportunity varies.

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)

Ac-225-PSMA-617 (update)

We now have some details of the clinical trial of Ac-225-PSMA-617 in advanced prostate cancer patients. Kratchowil et al. reported on 40 patients who received this treatment at the University of Heidelberg. All patients had failed multiple therapies and were expected to have 2-4 months median survival (see this link). They received 3 cycles of Ac-225-PSMA in two-month intervals.

• 11 patients did not complete 3 cycles
• 5 discontinued due to non-response
• 4 discontinued due to xerostomia (dry mouth)
• 2 did not survive 8 weeks.

Among the 38 surviving patients:

• 87% had some PSA decline
• 63% had a PSA decline greater than 50%
• Tumor control lasted 9.0 months (median)
• 5 patients had a response lasting more than 2 years
• Previous therapies with abiraterone lasted 10.0 months, docetaxel lasted for 6.5 months, enzalutamide for 6.5 months, and cabazitaxel for 6.0 months

These outcomes are impressive for a therapy given when all other therapies have failed. It is unclear whether it is better than Xofigo, the only approved radiopharmaceutical for metastatic castration-resistant prostate cancer. Xofigo only attacks cancer in bones, whereas Ac-225-PSMA attacks prostate cancer anywhere in the body.

(Update 5/19/2019)

Sathekge et al. reported the outcomes on 73 mostly chemotherapy-naive and abiraterone/enzalutamide-naive metastatic castration-resistant patients treated with Ac-225-PSMA-617 in South Africa. Most patients had 3 treatment cycles (every 2 months). Subsequent doses were lower to prevent side effects. PSA and metastatic activity was tracked using Ga-68-PSMA-617 PET scans.

• 83% of patients responded to treatment
• in 70% of patients, PSA declined by over 50%
• PSA declines of over 50% predicted longer progression-free survival and overall survival
• In 29% of patients, all lesions disappeared
• During follow-up, 23 patients (32%) had disease progression and 13 (18%) died of prostate cancer
• Progression-free survival was 15 months (median)
• Overall survival was 18 months
• Xerostomia (dry mouth) occurred in all 85% of patients, but it was not severe enough to stop treatment
• Anemia occurred in 27 patients (37%); none grade 4
• Grade 3 or 4 renal toxicity occurred in 5 patients with pre-existing renal impairment

This study suggests that Ac-225-PSMA-617 can be beneficial in patients who have not been heavily pre-treated. It also shows that xerostomia can be mitigated by reducing the subsequent doses given, and that for most patients, side effects are not severe enough to stop treatment. Lu-177-PSMA is now in a Phase 3 clinical trial at multiple sites in the US.

Are two PET radiotracers better than one?

There seem to be clinical trials of new PET radiotracers for the detection of prostate cancer all the time. In addition to the FDA-approved C-11 Choline, NaF18, FDG, and fluciclovine PET scans, most of the new PET scans target the PSMA protein on prostate cancer cells. On the horizon, we have seen some encouraging reports on PET radiotracers that target the Gastrin Releasing Peptide Receptor (GRPR) with a peptide called bombesin. GRPR, as the name implies, is ubiquitous in the stomach and intestines, but seems to show up in several different kinds of cancer cells as well.

Zhang et al. reported the results of a very small pilot study using a synthetic molecule that targets two different receptor proteins at the same time (also see this link). One part of the molecule (bombesin - BBN) targets the GRPR protein. The other part, called RGD, targets a protein called αvβ3. αvβ3 is a member of a family of proteins called integrins. These proteins are responsible for maintaining the structural integrity of cells. αvβ3 promotes cell adhesion, spreading and blood supply -- qualities vital to metastatic progression.

They used both the single Ga-68-BBN PET/CT and the dual Ga-68-BBN-RGD PET/CT to detect prostate cancer among 13 patients (4 newly diagnosed, 9 recurrent) with biopsy-proven prostate cancer. The dual PET radiotracer found cancer:

• In the prostates of 3 of the 4 men with newly diagnosed prostate cancer vs. 2 of the 4 men using the BBN-only radiotracer.
• 14 metastatic lymph nodes vs. 5 metastatic lymph nodes using the BBN-only radiotracer.
• 20 bone metastases vs. 12 metastatic bone metastases using the BBN-only radiotracer.

There were no toxic reactions.

While encouraging, it is still very early to draw conclusions. There is no confirmation that the extra "metastases" discovered were indeed metastases - they may be false positives. And there are no clues as to which kinds of prostate cancer the dual PET radiotracer is sensitive to, and which kinds are undetectable.

If confirmed by larger studies, it may be possible to not just detect the cancer, but to kill the detectable cancer cells as well with beta emitters like Lu-177 or alpha emitters like Ac-225.

The synergy of combining radiation and immunotherapy in the treatment of prostate cancer

(updated)

Finkelstein et al have written an excellent review of the current understanding of this emerging and complex field. In contrast to some earlier studies that showed that radiation depressed the gamut of white blood cell types (e.g., Johnke et al, 2005), recent studies have shown that any such radiation-induced leukocyte suppression in high risk men is temporary, and there is a long-lasting enhancement of the anti-cancer immune response. The discrepancy with earlier findings may be due to higher doses of radiation used now, or the higher-precision radiation fields. There is also some evidence that the effect may vary with the kind of prostate cancer, the phenotype, associated with different risk levels, pelvic lymph node radiation, and by the way the dose is given (e.g. LDR brachytherapy vs SBRT). 

In fact, the authors find the opposite of the conventional wisdom to be true: radiation has an immune stimulatory effect when used on men with high-risk prostate cancer. There is an opportunity to bolster this effect when treating high-risk men with radiotherapy -- initial prostate radiation, salvage radiation after surgery, or radiation to isolated metastases. If this effect is maximized, there is a hope of killing off systemic micrometastases and tumors well outside of the radiation field. This is called the abscopal or bystander effect.

Radiation kills cancer cells, and the cellular debris is a source of antigens. Dendritic cells learn to use those antigens to activate killer T cells that then seek out and destroy cancer cells elsewhere that express those antigens. The damaged cancer cells also signal a host of other tumor-toxic molecules to form. Radiation-modified cancer cells that escaped direct annihilation become more immune-susceptible too.

"Immune exhaustion"  has been raised as one reason why the immune system fails at combating cancer. Reducing the tumor burden with SBRT has been found to increase immune response in patients with melanoma.

Provenge, a dendritic cell boost coupled with immune-stimulatory factors, seems to be a perfect companion to radiation. There is a randomized clinical trial (NCT01807065) at the City of Hope to determine whether Provenge's effectiveness is enhanced by radiation to a single metastasis in men with mCRPC. [Update 2019:] Twardowski et al. reported that progression-free survival was 3.7 months among those who received Provenge after SBRT vs. 2.5 months if they received Provenge without SBRT. This did not reach statistical significance (p=0.06) on this small sample (about 25 in each arm).[Update June 2022:] Hannan et al. reported on 20 mCRPC patients who received Provenge and SBRT to 1-5 oligometastatic metastases. The combination did not retard progression compared to historical controls.

(Update 2/2020) A small trial randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. Xofigo (radium 223 chloride) is a radioactive drug that destroys bone metastases. After median follow-up of 5.3 months:

• Median progression-free survival was 10.7 months for the combination vs 3.1 months for Provenge alone.
• The % who had a PSA reduction by more than half was 33% for the combination vs 0% for Provenge alone
• 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

But immune stimulation will never be longlasting. 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: Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor). "Ipi"+ radiation for mCRPC has been tried in two pilot tests. In one, patients were given radiation to a single bone met followed by ipi or a placebo, but the addition of ipi did not significantly increase survival.  In another study, patients were randomly assigned to get ipi+radiation or ipi alone. Both the PSA and the bone met response was good, and about the same for both groups. A larger study in 799 patients of ipi + radiation vs radiation alone confirmed the lack of effect (except in select subgroups) with 10 months of follow-up , but...

(update 8/2020) There was better news after the 799 patients were followed for a longer time. In an update by Fizazi et al 2.4 years later, ipi did increase survival in mCRPC patients, all of whom already had docetaxel, who received a single dose (8 Gy) of radiotherapy (SBRT) to one or up to 5 bone metastases. The effect reversed over time.

• From 0-5 months post-SBRT, survival was 49% worse among those who got ipi
• After 5 months post-SBRT, survival was ⅓ better among those who got ipi
• At 2 years, survival was 25% with ipi vs 17% without ipi
• At 5 years, survival was 8% with ipi vs 3% without ipi
• Ipi drug toxicity caused death in 7 patients
• The effect was the same for those with ≤5 or >5 bone metastases

It may be that those who died in the first few months were already beyond being helped, and the ipi toxicity harmed rather than helped them. Ipi alone has been found to have no effect on survival of mCRPC patients, even when used before docetaxel (see this link). SBRT to bone metastases has not been shown to increase survival (this is the subject of ongoing clinical trials). It is encouraging that the combination has some effect.

(Update 10/6/21) Kwan et al. reported the results of the Phase II ICE-PAC trial combining SBRT of metastases with the immune checkpoint blocker avelumab in 31 mCRPC men in Australia.

• "Disease Control," defined as complete response, partial response, or stable disease, was realized in about half the patients.
• Only 16% suffered serious (Grade 3 or 4) toxicity and only 10% had to discontinue avelumab.
• Response was independent of the number of metastases that were irradiated.

A new immunotherapy, ProstAtak, is being tested with radiation for localized PC (NCT01436968).

Some have suggested that several hypofractionated doses of radiation maximize the immune effect. To that end, UVA initiated a clinical trial (NCT02284971) of an experimental immune stimulant, Varlilumab, coupled with SBRT in 5 doses to the prostate and/or metastases in men with CRPC; however, the trial was terminated due to low accrual.

Other immune stimulants, like Leukine, have been used effectively in mice, and by some clinicians in human patients. It is likely that the optimal immune combo with radiation will include a front-end stimulant and a back-end checkpoint blocker.

Adding androgen blockade may enhance the immune effect still further (Antonarakis & Drake), and radiosensitize the tumors.

There are many unanswered questions:

• Will the abscopal effect be any better in men who are metastatic but still hormone sensitive? 
• Is the abscopal effect maximized with both dendritic cell enhancement and checkpoint blockade, or is the combination too toxic? 
• Does Keytruda work better than Yervoy? 
• What is the optimal timing of radiotherapy and immunotherapy? Should Provenge be used before, during, or after radiotherapy? 
• For how long is the abscopal effect sustained? 
• Is there still an abscopal effect when lymph nodes are irradiated? 
• Does the abscopal effect increase with the number of metastases irradiated? 
• Is there an abscopal effect with Lu-177-PSMA (this is the subject of a clinical trial at UCSF)?
• Will a PARP inhibitor further enhance the abscopal effect? 
• Can the abscopal effect be utilized for rare types of prostate cancer (e.g., neuroendocrine or undifferentiated)? 
• Are there any genomics or biomarkers that are predictive or prognostic? 

written December 25, 2014 and updated since

SBRT Dose Escalation

Is there an optimum treatment dose for SBRT? At the low end of the spectrum, Alan Katz found that 35Gy in 5 fractions gave equivalent oncological outcomes with less toxicity compared to 36.5 Gy. At the other end of the dose spectrum, a clinical trial pushed the dose as high as 50 Gy in 5 fractions with disastrous consequences (see this link).  A trial of high dose rate brachytherapy, which is radiologically similar to SBRT, failed to find an optimum dose.

But radiation safety is not only just about dose. We saw that two treatment schedules using the same prescribed dose (40 Gy in 5 fractions) had disparate toxicity outcomes (see this link). In fact, the 12 month toxicity outcomes of Dr. King's high-risk study were recently presented and look excellent (see this link). It's also worth noting once again the outcomes of the 5-year multi-institutional SBRT clinical trial that used 40 Gy in 5 fractions and had excellent oncological and toxicity outcomes (see this link).

Helou et al. reported the outcomes of their SBRT (they call it SABR, but it's the same thing) trials at the Sunnybrook Health Sciences Centre in Toronto, Canada. There were sequential trials conducted from 2006-2014:

• 35 Gy/5 fractions/29 days - 82 low risk men only
• 40 Gy/5 fractions/11 days or 29 days - 177 low and intermediate risk men

A few (12) men had up to 6 months of androgen deprivation to shrink their prostates prior to radiation.

As an early measure of oncological effectiveness, they used PSA at 3 years (PSA3Y) after radiation. After correcting for the other variables like age, baseline PSA, T stage, and ADT use, the dose received remained the biggest predictor of PSA3Y. Median PSA3Y was:

• 0.64 ng/ml in those who received 35 Gy
• 0.27 ng/ml in those who received 40 Gy
• The difference was significant in both low risk men and intermediate risk men

The use of PSA3Y as a surrogate endpoint for biochemical recurrence is controversial. Because prostate cancer progresses very slowly and radiation, at the very least, reduces the cancer burden, it can take at least 5 years, and as long as 10 years, before we start to see concrete evidence that such therapy is curative. Also, a longer time until the nadir is achieved has been found to be correlated with failure-free survival (see this link). Nadir PSA has been proven to be a strong predictor of a lasting cure (see this link), but no one can tell when the nadir will be reached. In a recent study comparing the PSA at 1000 days after SBRT or HDR brachytherapy to the PSA at 1000 days after conventional IMRT, Kishan et al. reported that the PSA was lower for SBRT/HDR-BT. While the downward slope was about the same for the first 1000 days, the slope was steeper afterwards for SBRT/HDR-BT, indicating that a lower nadir would be achieved.

After correcting for confounders like age, baseline urinary function, and time between treatments, late term urinary toxicity of grade 2 or higher was 17 times greater among those who received 40 Gy compared to those who received 35 Gy.

The authors previously reported late term rectal toxicity. After 2 years, the cumulative probability of  grade 2 or higher rectal toxicity was suffered among:

• 5% of the men who received 35 Gy with 4mm margins
• 27% of the men who received 40 Gy with 5 mm margins
• 42% of the men who received 40 Gy with 5 mm margins +  30 Gy to seminal vesicles received 

Grade 3 and 4 rectal toxicity was especially high (10%) in the group that had their seminal vesicles irradiated. There were 3 cases of fistulas that may be attributable to rectal biopsies. [Patients should be very careful about the use of any kind of instrumentation within at least 6 months of radiation. That includes cystoscopies and colonoscopies.] Since this study, the authors have changed their radiation planning to include faster (VMAT) linacs and improved rectal dose constraints. Other changes that might mitigate rectal toxicity may include use of intrafractional tracking, rectal immobilization, and a rectal spacer.

There was clearly a trade-off between SBRT dose and late-term side effects of treatments. Perhaps we will one day be able to identify those cancers that are curable with a lower dose, and treat only those with the more radio-resistant cancers with a higher dose. Some believe that such techniques as simultaneous integrated boosts or heterogeneous planning may cure the cancer in the prostate better with less damage to organs at risk. But they remain to be proved in randomized clinical trials.

Note: Thanks to Dr. Andrew Loblaw for allowing me to review the full text of the study.

If you are using PSA to monitor your cancer, you may want to avoid curcumin (and some other supplements)

Curcumin (a turmeric extract) is one of the most popular natural substances subjected to pre-clinical research. Based on mouse and lab studies, it has been touted as the cure to cancer and just about everything else, with reports of activity including anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, antioxidant, immunomodulating, anticarcinogenic, and Alzheimer’s disease, among others. This "panacea" and the low level evidence behind it are satirized in this amusing video.

It is one of the most widely researched supplements - in mouse and lab studies. In spite of its spectacular success with mice, randomized clinical trials in humans have been lacking. Choi et al. reported on a double-blinded randomized clinical trial of curcumin on 82 evaluable men who completed one treatment cycle of intermittent hormone therapy. They were then given 1440 mg/day of curcumin or a placebo for 6 months. The goal of the study was to see whether curcumin could extend their time off of hormone treatment.

• Those taking curcumin were able to avoid hormone therapy for 16.3 months
• Those taking the placebo were able to avoid hormone therapy for 18.5 months
• The difference was not statistically significant
• 10% of patients taking curcumin had PSA progression during the curcumin treatment period vs 30% of those taking the placebo.

The fact that those taking the placebo had an insignificantly longer break from hormone therapy in spite of the fact that their PSA progression was greater than those who were taking curcumin in the first 6 months, indicates that curcumin may have interfered with the PSA tests while they were taking it. Clearly, curcumin did not delay clinical progression.

Ide et al. found in a small (n=85) double-blind randomized clinical trial that a mixture of soy isoflavones and curcumin suppressed the serum PSA readings of men with high PSA (>10 ng/ml) who were confirmed by biopsy to not have prostate cancer. The curcumin mixture suppresses the PSA reading independent of prostate cancer.

A multi-center, blinded randomized clinical trial in France of curcumin+docetaxel compared to docetaxel alone in men who were metastatic and castration-resistant was ended early because of futility. Although not statistically significant, combining docetaxel and curcumin consistently gave worse outcomes (progression, survival) than docetaxel plus placebo.

Fabiani et al. reported on 50 consecutive patients with PSA over 4.0 ng/ml or PSA velocity > .75 ng/ml/year. They were given curcumin for 30 days.

• Baseline % free PSA was 17%
• After 30 days of curcumin, % free PSA was 20%
• The changes in PSA and % free PSA were statistically significant

It seems that curcumin suppressed PSA. Although it is possible that 30 days of curcumin reversed the prostate cancer, that is unlikely. It is more plausible that curcumin affected the PSA assay.

This effect has been noted in the literature. The authors of this analysis and this one label curcumin as a Pan-Assay Interference Compound (PAINS), which means that it is known to interfere with assay readouts. Curcumin particularly confounds tests of molecules, like prostate specific antigen (PSA) and prostate-specific membrane antigen (PSMA), that penetrate the cell wall. According to this analysis, other common supplements that may interfere with the integrity of the cell wall without actually binding to a site on the proteins (which would be a real drug effect) include genistein (a soy isoflavone), EGCG (green tea), resveratrol (grapes),  and capsaicin (chili peppers).  Some of these compounds, including curcumin, are capable of forming stable metal ion complexes and should be scrupulously avoided by patients taking Ga-68-PSMA-11, Lu-177-PSMA-617, technetium bone scan, or gadolinium MRI contrast agent. Glutamate (MSG used in Chinese food) is also a powerful chelator. It has been found to markedly decrease the effectiveness of PSMA theranostics (see this link).

There are other supplements that may mask PSA readings without affecting progression. These include saw palmetto, pygeum, and beta-sitosterol. 5-alpha-reductase inhibitors (Proscar and Avodart) affect PSA in men with BPH and prevent the occurrence of prostate cancer. Because they affect PSA in a known way in men with BPH, we are able to correct for the PSA aberration (by doubling the PSA reading). The FDA has warned that biotin, in many multivitamin preparations, may interfere with many laboratory blood tests. Men taking statins should also be aware that it may produce artificially low PSA readings (see this link and this one). Statins, which seem to be beneficial in some observational studies but not in others, may only have an apparent benefit because of masking of PSA, as in this study and this study.

In designing future clinical trials on curcumin, like this one or this one that tests its benefit as an adjuvant therapy to active surveillance, it is important that the measured endpoint not be dependent on PSA. PSA doubling time, biochemical recurrence-free survival, and time before ADT is initiated (which is usually given as a result of increasing PSA) are artificially increased by curcumin. Only endpoints like radiographic progression-free survival and metastasis-free survival are useful. Incidentally, this is also why those endpoints must be chosen when evaluating the effectiveness of metastasis-directed therapy, which will lower PSA arising out of macroscopic metastases but may or may not slow the cancer's progression.

I spent a very short career as a chemist developing radioimmunoassays for biological substances, like PSA, that were only detected in serum in nanomolar and picomolar amounts. I can attest that even small amounts of impurities that adsorb, quench fluorescence, or react with the protein or its antibody can completely invalidate a test. Curcumin seems to do this.

The biggest problem with curcumin as a medication is its oral bioavailability, which is less than 1% and its elimination half-life, which is about a half hour in rats. It is doubtful that enough is bioavailable to have any therapeutic effect. This is true in spite of substances like piperine that aid passage through the gut wall. It is metabolized very quickly by the liver. Moreover, what is actually in a pill labeled as curcumin is highly variable, and curcumin is chemically unstable.

Many men rely on PSA to monitor prostate cancer progression. It may be misleading to use a supplement that may invalidate this important test. If there were any valid clinical studies indicating a true benefit, the corruption of a biomarker might be forgivable. But curcumin has only shown a benefit to mice so far. There are also some safety concerns (see this link). Patients must be wary of any supplement whose benefit is only supported by mouse/lab studies, and which only seems to affect PSA measurements. It is entirely possible to treat PSA without actually treating the cancer.

Is overall survival a useful endpoint for evaluating therapies for intermediate risk patients?

In a recent commentary, we looked at the utility of surrogate endpoints in evaluating therapies. In an abstract presented at ASCO, Malouf et al. examined the large National Cancer Data Base to determine whether there is an association between the use of brachytherapy (BT), external beam radiation (EBRT), or a combination of both (CT) and overall survival in intermediate risk patients.

They found records on 122,405 patients treated from 2004-2013 who were staged IIA. IIA is an AJCC risk category that is similar to the NCCN intermediate risk category, except that it excludes those clinically staged with cancer in both lobes (stage T2c). The average age of the patients at diagnosis were:

• ·      EBRT: 69 years of age
• ·      BT and CT: 66 years of age

The study provides no information about the radiation doses used.

The average survival, and the percent who survived 10 years were:

• ·      EBRT: 109 months, 61.5%
• ·      BT: 116 months, 72.9%
• ·      CT: 116 months, 73.1%

Survival differences were statistically significant between EBRT cohort and those who received the two other therapies.

The authors conclude:

“The method of radiotherapy used contributes to the survival of patients with stage IIA prostate cancer, with brachytherapy with or without EBRT having improved survival. Careful selection of the proper treatment regimen should be used.”

Now, when we look at US actuarial tables, we see the expected survival for a 66 year-old man is 16.93 years (203 months), and 14.81 years for a 69 year-old man (177 months). So the men treated with EBRT should have lived 26 months less; yet they lived only 7 months less – a relative survival gain for some unknown reason. It is also unknown why overall survival in both cohorts was so much less than actuarial expectations.

Using the Memorial Sloan Kettering nomogram for life expectancy where intermediate risk cancer has been diagnosed but not yet treated, and assuming no significant co-morbidities or risk factors, and allowing only for the difference in age, the expected 10-year survival statistics for untreated prostate cancer are as follows:

Among the 66 year old men (BT and CT cohorts):

• ·      71% would still be alive, which is close to the observed 73% among those who were treated
• ·      20% would have died of other causes
• ·      9% would have died of prostate cancer

Among the 69 year old men (EBRT cohort):

• ·      67% would still be alive, which is somewhat higher than the observed 63% among those who were treated
• ·      25% would have died of other causes
• ·      8% would have died of prostate cancer

What we learn from this is that for a man who has a life expectancy of ten years or less, watchful waiting may be a better choice than radical treatment.

We see that it is impossible to attribute the difference in the overall survival to prostate cancer, let alone to any of the treatments received. What we needed to know is prostate cancer-specific mortality, and we have no idea from their analysis how, if at all, it was affected. Because of the very low rate of prostate cancer-specific mortality at 10 years, even in untreated patients, it takes a very long time to be able to detect differences in the efficacy of various treatments based on this endpoint; hence, the importance of surrogate endpoints. The authors’ conclusions are completely unfounded based on the data they presented.