The Perils and Pitfalls of "Treating PSA" in Advanced Prostate Cancer

Prostate Specific Antigen (PSA) is a protein on the surface of all benign prostate cells and most malignant prostate cancer cells. In prostate cancer, expression of PSA is correlated with the size of the tumor (see this link). When prostate cancer first metastasizes, the tumor is limited in size by its blood supply. As it grows, the cancer creates its own blood supply by secreting growth factors called VEGF. The PSA from the cancer activates VEGF to form blood vessels that bring oxygen and nutrients to the cancer and lymph vessels to drain fluids from the growing tumor (see this link). Tumor blood supplies are not as patent as those of benign tissues. Healthy prostate tissues with patent blood supply, and micrometastases that have little or no blood supply put out very little detectable PSA into the serum (although the cells express high levels of PSA). But the leaky blood supply of tumors allows PSA to enter the serum where it is detected by a PSA test. So, the larger, more established tumors of a given patient create almost all of his detectable PSA (see this link).

"Treating PSA"

I. Selecting for low PSA subtypes

For most men with advanced prostate cancer, PSA is their best biomarker of progression - more detected PSA means more progression. This may change as the cancer evolves. A highly mutated tumor may put out less PSA. Highly undifferentiated kinds of prostate cancer, and other relatively rare sub-types (e.g., ductal, neuroendocrine, basal cell, "double negative," etc.) may evince little or no serum PSA.  

So it is possible, when such phenotypes are present and they are mixed with "normal" prostate cancer, to provide treatments that kill off the "normal" prostate cancer cells, leaving the low-PSA subtypes behind. Such a situation has been identified in patients heavily treated with chemo and enzalutamide. It is called "treatment-emergent neuroendocrine prostate cancer" (see this link) and has been identified in 17% of heavily-treated patients. 

Another example of a treatment that may select for low-PSA subtypes is Lu-177-PSMA. If the patient has two types of prostate cancer, one that expresses PSMA and PSA, while his other cancer expresses neither, PSMA-targeted therapy may eliminate the source of most of the PSA, leaving more virulent subtypes behind (see this link). 

This type of situation is dangerous if one relies on PSA as the principal biomarker of progression. One may be lulled into complacency by deceptively low PSA.

It is worth noting that two FDA-approved therapies for prostate cancer, Provenge and Xofigo,  have been proven to increase survival, but have little or no effect on PSA.

II. Supplements that interfere with PSA tests

Patients often self-medicate in the hope of wresting some control over their cancer. The internet is full of "evidence" that this or that natural supplement may slow progression or even cure the cancer.  Serum PSA is detected by an antibody that can detect amounts as low as a nanogram of PSA per ml of serum. This kind of sensitivity has a cost - the antibodies are subject to interference by other substances that may be present in the serum. So far, the list of substances that may interfere with PSA tests, creating false negatives, includes biotin, curcumin, genistein, EGCG, resveratrol, capsaicin, saw palmetto, pygeum, beta-sitosterol, and statins (see this link). The false negative PSA readings may fool the patient and his physician (who may not be aware of the patient's supplement use) into believing that the cancer is under more control than it really is. Patients who use any complementary therapies are twice as likely to die of their cancer (see this link).

III. SBRT of oligometastases

1. Exponential growth

Because of Covid-19, many of us are now used to seeing exponential growth curves. Deaths from Covid-19 started very slowly in December through February. But then in March, the number of deaths climbed markedly. This illustrates the two striking features of exponential growth - the "flat" part with a very slow increase, followed by a "steep" part with a very rapid increase.

Among the biological systems that also follow an exponential growth curve are bacteria, viruses, and cancers. Here is a prototypical graph of the number of metastases in a patient.

In men who are PSA-recurrent after prostatectomy, it takes a median of 8 years for the first metastasis to become detectable (see this link). After that, I've seen that more than a year can go by between the detection of the first metastasis and the next one. Some researchers, who should know better, observed that in their patients who had early metastases treated with radiation, new metastases did not occur for a long time. They attributed the delay to the treatment rather than the natural history of metastatic progression  (see this link). It is impossible to know if there was a delay in progression without a randomized clinical trial.

What is really happening during this extended time period? The accepted theory is called "seed and soil." There are millions of cancer "seeds" in the serum, the lymph, around nerves, and hiding in various tissue reservoirs (mainly in bone tissue). While they appear to be quiescent, they are in fact changing the "microenvironment" of the tissue they are in. They are transforming the tissue to make it more conducive to prostate cancer growth, building networks of collagen, fat, blood vessels and nerves, influencing healthy cells to become cancerous, and preventing the immune system from destroying the new nests (see this link for a fuller explanation).

Because it takes such a long time to build up the metastases to the point that they are detectable by even our most sensitive PET/CT scan (the tumor detection limit is about 4 mm - millions of cells), it seems that there is little there and even less going on. This is called "oligometastatic" cancer. It seems like all the cancer can be picked off by playing whack-a-mole -- zapping the few detected metastases with intense radiation (called SBRT) as they are detected. In fact, it is well-established that SBRT provides excellent "local control." "Local control" means that the metastases are usually completely annihilated by just one or two "zaps" (see this link). Because the detected metastases are the source of almost all the PSA, PSA can fall to undetectable levels after such treatment of oligometastases. But the cancer is far from cured - the PSA has been treated, but the cancer is still micrometastatic and systemic.

Those who believe that such treatment can result in a durable remission believe that the immune system can clean up the rest of the cancer.  The ORIOLE trial (reviewed here) showed that SBRT created a T-cell response. If that T-cell response is sustained, they argue, the activated immune system can "clean up" the rest of the cancer. The skeptics argue that T-cell responses are usually not sustained. Trials of numerous immunotherapies (e.g., Prostvac, GVAX, GM-CSF, etc.) have failed to show a benefit because the early T-cell responses are countered by adaptive responses. Prostate cancer is notoriously "cold" to immunotherapies.

2. PSA-based Endpoints

What we really want to know is this: will the treatment enable patients to live longer? Overall survival is the gold standard of success of randomized clinical trials. The "problem" for clinical trials is that prostate cancer is such a slow killer, that it may take 15 years or more to discern a difference (see this link) if patients have localized or recurrent prostate cancer at the start. (For most other types of cancer, 5-year overall survival is more than adequate.) Clinical trials are often ended when half of the control group die (median survival). But, depending on patient characteristics at the start, median survival may never be reached within the duration of the clinical trial (see this link and this one and this one).

Prostate cancer-specific survival (how long before patients succumbed to their prostate cancer) is little better. It is also hampered by the fact that patients with prostate cancer may die of something else sooner, possibly because their cancer was debilitating. It is often unclear to the doctor who signs the death certificate whether the cancer was the end cause, a contributing cause, or a non-contributing factor. To get clinical trial results before new medical science and technology renders the results irrelevant, we want to use surrogate endpoints that are highly correlated with and predict overall survival.

The earliest endpoints that can be used to measure the success of a prostate cancer therapy are PSA based. All of the following surrogate/secondary endpoints are PSA based:

• PSA50 - the percent who had a reduction in PSA by 50% or more
• Nadir PSA - the lowest PSA reached after therapy (see this link)
• PSA doubling time (PSADT) - whether the therapy slowed PSA growth
• Biochemical recurrence (BCR) - depending on initial treatment, and there may be multiple salvage therapies, each with a PSA failure defined for it (see this link)
• Biochemical Recurrence-Free Survival (bRFS)
• Biochemical Disease-Free Survival (bDFS)
• Biochemical failure (BF)- rise in PSA by a pre-specified amount post-therapy
• Biochemical No Evidence of Disease (bNED)
• Time to BCR/ BF
• Time to start of lifelong ADT (based primarily on a pre-defined PSA failure benchmark)
• Failure-free survival (FFS) or Progression-free survival (PFS) or Event-free survival (EFS) - defined as BF or radiological progression or clinical progression or death. 

The following surrogate endpoints are not PSA-based:

• Clinical Progression-Free Survival (cPFS) - worsening of symptoms or performance status (see this link)
• Radiographic Progression-free Survival (rPFS) or Disease-free survival (DFS)- progression on scans or death
• Objective Response Rate (ORR) - tumor size or number reduction using RECIST criteria
• Change in Bone Scan Index
• Time to radiographic progression or failure
• Metastasis-free survival (MFS)
• Clinical progression - pain, bone fracture, spinal compression

As an example of circular reasoning, we can see in the ORIOLE trial that 6-month Progression Free Survival (PFS) was chosen as the primary endpoint. PFS was defined as  PSA progression (by >25% over nadir and by > 2 ng/ml) or radiographic progression or death. As we can readily see in the exponential growth curve, the odds of a new metastasis on a bone scan/CT are very low and there are not likely to be any deaths. Therefore, PFS was almost entirely PSA progression. But the protocol "treated PSA." It is therefore illogical to conclude, even for a Phase II trial, that oligometastatic treatment slowed progression.

(Update 8/25/2022) Deek et al. combined ORIOLE and STOMP (n=162) with extended follow-up. After 52.5 months of median follow-up, they report:

• Progression-free survival (PFS) was 11.9 mo. for metastasis-directed therapy (MDT) vs. 5.9 mos. for observation. (HR=0.44)
• Radiographic progression-free survival (rPFS) was not significantly different
• Time to castration resistance was not significantly different
• Overall survival was not significantly different
• PFS increased by about 5-6 months regardless of whether there were high-risk mutations (BRCA, ATM, RB1, TP53).
• rPFS did not significantly increase for either group.

What is confusing is the endpoint used in this analysis. 

Progression-free survival (PFS) = 

1. a PSA rise, or 
2. radiographic progression, or 
3. new symptoms, or 
4. initiation of ADT, or 
5. death.

In 52.5 months, there was very low mortality (5), and asymptomatic local control is good (3). Initiation of ADT (4) is always based on either rise in PSA (1) or radiographic progression (2). So with no difference in rPFS, the difference between PFS and rPFS is just PSA. This suggests that the extended follow-up found that MDT only treated PSA without any real impact on survival or progression of the cancer.

(Update 10/26/2022) Another example of circular reasoning can be seen in the EXTEND trial from MD Anderson. They randomized oligometastatic patients to receive metastasis-directed therapy (MDT) + ADT or ADT alone. They only evaluated "progression-free survival" which, at 22 months, was almost entirely lack of PSA progression. They claimed that the lack of PSA progression made it safe to give patients a break from ADT.

It is worth noting that radiation of the prostate ("debulking") has no survival or progression advantage when there are multiple metastases, only when the metastatic burden is low (see this link). The prostate is, of course, the source of all metastases, and an ideal environment for metastases to develop and grow. Metastasis-to-prostate spread has been observed. In a meta-analysis of the two debulking trials called STOPCAP M1, researchers found that there was a statistically significant reduction in PSA progression (by 26%), even when there was no benefit in terms of metastatic progression or survival. Treating PSA even by debulking the entire prostate is not in and of itself of any oncological benefit (there may be a palliative benefit, however).

3. Danger of Withholding Early ADT

While ORIOLE, STOMP, and SABR-COMET were Phase 2 clinical trials whose results were not meant to change practice, many patients and their doctors (often under pressure from patients) would like to believe they do. If the metastases are in places that are safe to irradiate (e.g., away from the mediastinum), there is little risk in doing so. However, if they do not understand the circular reasoning evident in the ORIOLE trial, they may put off therapies that are known to increase survival. There is also a risk of unreasonable expectations.

Some patients (and doctors) believe that by delaying ADT, they can increase their quality of life, and delay castration resistance. Neither is true. Contrary to popular belief, decreasing the intensity of hormone therapy and delaying its use brings earlier castration resistance and death. The strongest evidence for this comes from the STAMPEDE (on Zytiga and Xtandi), LATITUDE, and SPARTAN trials. Among men who were newly diagnosed with metastatic prostate cancer:

• Overall survival was longer if men used Zytiga + ADT.
• No difference based on the number of metastases
• Failure-free survival was longer if they used Zytiga  + ADT
• Overall survival was longer if men used Xtandi+ADT
• Survival was especially lengthened if there were fewer metastases 
• PSA progression-free survival was longer if they used Xtandi+ADT
• Overall survival was longer if men used Erleada+ADT
• PSA progression-free survival was longer if they used Erleada+ADT

A clear pattern emerges: early use of intensive hormone therapy prolongs survival and prolongs the time to castration resistance. Men who were oligometastatic benefited from early, intense hormone therapy.

The TROG 03.04 RADAR trial examined the duration of hormone therapy in high-risk men treated with radiation.  They found that, after 10 years of follow-up, men treated with 18 months of ADT survived longer, and reached castration resistance later compared to men treated with 6 months of ADT.

The TOAD trial looked at starting ADT at the first sign of recurrence vs. waiting for metastases to be detected. Men treated earlier reached castration resistance later. It also showed there was no major detriment to global health-related quality of life by starting ADT earlier (see this link).

Maha Hussain reported the results of a randomized clinical trial comparing intermittent vs continuous ADT in recurrent men with metastases. She found that:

• Time to castration resistance was not different for the two protocols (Figure S5)
• For men with minimal disease, overall survival was 6.9 years for those on continuous therapy vs 5.4 years for those on intermittent therapy. The trial was underpowered for this difference to reach statistical significance.
• It took 4-5 years for the survival curves to start separating - long follow-up is needed to detect survival differences.

Taken together, all these major randomized clinical trials show that the best way to use ADT in the oligometastatic setting is to use it early and heavily. Reducing the number of cancer cells as quickly and effectively as possible, even reducing those cells that haven't begun to measurably contribute to PSA, extends survival. The effect of evolutionary selection pressure allowing castration-resistant cells to survive is dwarfed by the reduction in sheer numbers. Circular reasoning may harm patients.

4. Future Clinical trials

We have learned some lessons about clinical trials for oligometastatic treatment:

• It has to have long enough follow-up, depending on the setting: at least 5 years for  newly diagnosed or recurrent men to allow time to get to the steep part of the exponential curve. It will take longer if more sensitive imaging is used.
• It must use radiographic progression-free survival, or similar, as its primary endpoint
• It must not use a PSA-related endpoint
• ADT must be used in at least the control group. It would be unethical to withhold the standard of care (see AUA Guidelines for Advanced Prostate Cancer (mHSPC 14-18)) .
• It should preferably use a PSMA PET/CT to locate metastases. The ORIOLE trial only found an advantage if patients were oligometastatic on both a PSMA PET/CT and a bone scan/CT. The use of more sensitive imaging will move the starting point to the left on the exponential curve, so it will take that much longer to detect a benefit.

These randomized clinical trials (RCTs) are currently active:

• The CORE RCT at Royal Marsden Hospital in London will have 5 years of follow-up (completion in Oct. 2024) and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
• The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in April 2025) and has radiographic progression-free survival as its primary outcome. 
• The PLATON RCT (among hormone-sensitive patients) in Canada will have 6 years of follow-up (primary outcome in July 2025) and has radiographic progression-free survival as its secondary outcome. Oligometastatic men who have never had their prostates treated with RT will have prostate radiation too in both arms. ADT is given in both arms, advanced hormonals and chemo at the physician's discretion.
• The STEREO-OS RCT (study completion in Jan 2026) in France will look at radiographic progression-free survival with follow-up of up to 3 years. 
• The FORCE RCT at the University of Michigan (only recruited 13, primary completion in 2023) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful among men with mCRPC as it is in men with newly recurrent disease.
• The VA STARPORT RCT (primary completion in 2025) in many VA hospitals in the US will randomize patients to systemic therapy + PET-directed radiation to 1-5 oligorecurrences or to systemic therapy alone. Unfortunately, they are using castration-resistance as their primary endpoint, which is problematic.
• The START-MET RCT (primary completion in 2025) in Spain will randomize recurrent and newly diagnosed oligometastatic (≤3 on bone scan/CT and ≤5 on PSMA PET) men to standard-of-care (ADT+2nd line HT+prostate RT) or standard-of-care + SBRT to all metastases. 2-year radiographic progression is the primary outcome.
• The SPARKLE RCT (primary completion in 2027) in Belgium randomizes oligo-recurrent patients to either (1) MDT alone, (2) MDT+1 mo.of ADT or (3)MDT+6 mo (ADT+enzalutamide). Primary endpoint is 5 new lesions on PSMA PET scan.
• The ADOPT RCT (primary completion in 2022) in The Netherlands randomizes oligo-recurrent patients to either MDT ± ADT. 2.5 yr MFS on PSMA PET scan.

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

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

Michael Hofman reported the results of the TheraP randomized clinical trial (RCT). They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;

• mCRPC (PSA≥20 ng/ml and rising)
• must have had docetaxel
• must have had either Zytiga or Xtandi or both
• healthy, with good liver, kidney, and blood function

In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:

• Their metastases were insufficiently PSMA-avid - (10% excluded)
• There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
• 85 patients were treated with Jevtana
• 98 patients were treated with Lu-177-PSMA-617

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

• Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
• The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
• At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
• Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
• It is too early for data on overall survival (see below for update)
• Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% of those taking Jevtana
• The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, pain, nausea, dry mouth/eyes, low platelets, and anemia. Only 1 patient discontinued for toxicity.
• The most common adverse events reported by those taking Jevtana were fatigue, pain, diarrhea, nausea, loss of taste, neuropathy, dry mouth, and neutropenia, 3 patients discontinued for toxicity

(update 12/23) With longer term follow-up, it became apparent that although Lu-177-PSMA-617 was quicker to reduce PSA, there was no survival difference. After a follow-up of 36 months:

• Overall survival was 19.1 months for those starting with Jevtana vs 19.6 months for those starting with Lu-177-PSMA-617 (not statistically different)

This study further highlights the importance of getting both an FDG and a PSMA  PET scan at about the same time. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:

• Should it be used soon after second-line hormonals?
• Should it be used before or soon after docetaxel? (see this link)
• Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
• Should it be used in minimally metastatic patients?
• Should it be used in newly diagnosed metastatic patients?
• Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
• Will PARP inhibitors enhance the cell-kill rate?
• Is PSA the best biomarker of effectiveness?
• What are the best radionuclides to use (e.g., Ac-225, Th-227)?
• What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
• Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases?

Beyond PSMA - FAPI theranostics

(frequently updated)

Ideally, a new diagnostic and therapy ("theranostic") will have the following qualities:

• it will be theranostic for all cancer (high sensitivity)
• it will not be theranostic of anything that isn't cancer (high specificity)

In my previous article (see this link), we saw how PSMA heterogeneity can lead to treatment failure. PSMA is pretty specific, except for the salivary glands, the kidneys, and a few other places where expression is low. There is an opportunity to create ligands that are more sensitive and more specific.

Cancer is a tissue-based disease too

We often think of cancer as a cell-based disease: some rogue cells go wild, become immortal, and replicate out of control (see "The Hallmarks of Cancer"). In 1889, Stephen Paget put forth the "seed and soil" hypothesis: the cancer (the seed) thrives in "congenial soil." Not only does the seed find such soil, we have since learned that it actively creates its soil. This led to a new understanding of cancer as a tissue-based disease (see this link). What we call the "microenvironment" of the cancer is not just a passive player supporting the cancer cells; it actively sends signals to some cells (via extracellular vesicles - small "bubbles" containing microRNAs, enzymes, and essential proto-oncogenes) that cause them to become cancerous, and other cells to become supportive tissue - collagen, fat, blood vessels and nerves (collectively called stroma). They also suppress immune infiltration, attract regulatory T cells and certain kinds of macrophages that prevent immune response, and release cytokines that may cause or suppress inflammatory  response. The "reactive stroma" allows the tumor to grow and expand. This starts a positive feedback loop that enables the tumor (a collection of cancer cells and their stroma) to grow relentlessly.

Cancer-Associated Fibroblasts (CAF)

Fibroblasts are the most common cells in our connective tissue, which is the most prevalent tissue in our bodies. They create the collagen, fibronectin, the ground substance, adipose tissue, cytokines, growth factors, and other proteins that makes up the extracellular matrix that supports tissue architecture. When one cuts one's fingers, fibroblasts are activated and create the structure needed for the wound to heal. Fibroblasts are involved in cell adhesion, growth, migration and differentiation. Because they give rise to many different kinds of cell-precursers and proteins, they may be thought of as stem-cell-like (mesenchymal). The interested reader may wish to read this.

When cancer cells in the prostate go awry, they may, at some point go from being normal epithelial cells to being mesenchymal cells (called the epithelial-to-mesenchymal transition or EMT). EMT cells are capable of traveling outside of the prostate, where they can grow and clump into metastatic tumors, replete with cancer-associated fibroblasts (CAFs). The tumor can be thought of as a wound that doesn't finish healing and continually creates more wounds. In some cancers, 90% of the tumor volume is the stroma.

The tumor stroma can impair drug deliver, participate in drug resistance, and change the very nature of the cancer within (its phenotype). The stroma is where immunological agents and vascular-targeted agents have their effect (or lack of effect in the case of prostate cancer). See this link for a detailed discussion. It is also potentially targetable if it has a specific characteristic protein.

Fibroblast Activating Protein Inhibitor (FAPI)

There are several characteristic proteins in CAFs. One called Fibroblast Activating Protein (FAP) seems to be particularly useful. It is highly specific - it has only been found in cancers of epithelial origin (like prostate cancer), and never in healthy tissue. Immunohistochemical analysis of tumors has demonstrated a strong correlation between high FAP expression and worse prognosis. It has also been found in damaged tissue: inflamed tissues as in rheumatoid arthritis, myocardial infarction, liver cirrhosis, and atherosclerosis.

Uwe Haberkorn and researchers at the University of Heidelberg have synthesized a FAP inhibitor (FAPI) that seems to inhibit production of CAFs specifically and thoroughly.  Not only does it inhibit progression in mouse models, but it seems to "fix" the problems associated with the cancer stromal compartment - imperviousness to immunotherapies and angiogenesis inhibitors. They are fine-tuning the ligand to be more sensitive and specific, and to last long enough in clinical use for theranostic applications.

Kratochwil et al. reported on the Ga-68-FAPI uptake in 28 different tumor types in 80 patients, in whom FDG, PSMA or other PET scans failed to detect much cancer. Good uptake was seen for almost all solid tumors. Above average uptake was seen for sarcoma, salivary, esophageal, cholangiocellular carcinoma, breast, lung, prostate, pancreatic, thymus, head and neck, ovarian, desmoid, chordoma, and colorectal cancer.

Lindner et al. reported on two metastatic breast cancer patients treated with Y-90-FAPI-04 as a proof of concept. They both reported an immediate reduction in pain. Dr. Baum at Bad Berka has treated 10 patients with a single low dose of Lu-177-FAP-2286. It accumulated in tumors, and had no associated toxicity. There was some symptomatic relief in some patients, and he plans to give them a second injection.

It is also possible to target fibroblast growth factors using inhibitors rather than radioactive agents, as described in this article.

Recently, we saw how two PET indicators were more sensitive than one. In that study, a GRPR-targeted ligand was paired in the same molecule with an integrin-targeted ligand. Integrins are created downstream from fibroblasts. GRPR is found in prostate cancer cells but is also highly expressed in gastrointestinal and CNS tissues. This limits its usefulness as a therapeutic target. However, the concept of double therapeutic targets is potentially useful for prostate cancer, where both PSMA and FAPI may be targeted.

Clinical Trials

In the US, preliminary clinical trials of FAPI-targeted PET indicators have begun.

• This one  at Stanford
• This one and this one at UCLA

So far, there are no therapeutic trials of Lu-177-FAPI that I am aware of, although the Haberkorn group may well be doing exploratory work. Big Pharma has taken notice; Lantheus, Novartis, Clovis, and Avacta have announced investments.

There is also a fibroblast inhibitor, erdafitinib, being explored in clinical trials:

• This one at M.D. Anderson
• This one at UW Seattle

Why Lutetium-177-PSMA treatment sometimes may not help, and may even harm

(updated)

Lu-177-PSMA usually improves survival

We've seen in a couple of small trials in Germany and Australia that Lu-177-PSMA seemed to provide better than expected survival. In Germany, median overall survival was 12.9 months across 104 patients. In Australia, median overall survival was 13.3 months across 50 treated patients. In both trials, all or almost all patients had already received taxane chemotherapy and either enzalutamide or abiraterone. There was no control group in either trial, so we can only guess at what overall survival would have been without the therapy.

In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link),  median overall survival was 14.4 months with Xofigo vs. 11.3 months with placebo. The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival.

In a recent trial of Jevtana as a third-line therapy, after docetaxel and either abiraterone or enzalutamide, median overall survival was 13.6 months for Jevtana vs. 11.6 months for the other second-line hormonal. 

So, in heavily pre-treated patients, Lu-177-PSMA seems to improve survival about as well as Xofigo or Jevtana when used as a third-line therapy. The VISION trial  found that LuPSMA treatment increases survival by 5 months in heavily treated patients (similar to Xofigo).

PSA is not always a good indicator of effectiveness, as has been found for Xofigo and Provenge. Lu-177-PSMA reduced PSA in about 2/3 of treated patients in most studies. That leaves about 1/3 of patients who derived no benefit (even though they had PSMA-avid tumors), and waterfall plots showed that a few patients had large increases in PSA following PSMA-targeted therapy.

It is worth noting that the PSMA protein contributes to the survival of the cancer, and just the PSMA ligand that attaches to it has some activity in delaying progression, even without a radioactive component (similar to the way an anti-androgen attaches to the androgen receptor, delaying progression). It is also worth noting that ADT initially increases PSMA expression, but decreases its expression with continued use.

The opportunities are:

• to select patients who are likely to benefit
• give alternative therapies (like Jevtana) to patients who are unlikely to benefit
• provide adjuvant therapies that may increase survival

PSMA avidity - optimal point in time

It has long been known that PSMA is a moving target. The advent of PSMA PET scans has enabled us to track PSMA expression. Cancers that express a lot of PSMA (called PSMA-avid tumors) can be distinguished from cancers that express very little. Radiologists determine avidity by comparing the uptake of the tracer in cells that express PSMA to the uptake of the tracer in cells known to not express PSMA. Early low-grade prostate cancer does not express PSMA at all. Higher grade prostate cancer may express some PSMA. PSMA expression really starts to take off when the cancer metastasizes, although it is highly variable between patients. About 90-95% of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases. Treating when PSMA is not adequately expressed can cause a lot of toxicity to healthy tissues (especially kidneys and salivary glands) and little therapy (see this link and this one). Thus, there is an optimal point for treating each patient with PSMA-targeted therapy. Treatment too early or too late, may exert selective pressure on the predominant non-PSMA-types, allowing them to take over.

Michael Hofman and others at the Peter MacCallum Cancer Center in Melbourne (see this presentation and this link) have initiated several clinical trials using Lu-177-PSMA at earlier stages of disease progression:

• #lutectomy trial (Declan Murphy,  PI) is treating PSMA-avid high-risk patients with Lu-177-PSMA, followed by prostatectomy and pelvic lymph node dissection
• #upfrontPSMA (Arun Asad, PI) is treating patients first diagnosed with high volume metastases with Lu-177-PSMA + ADT + docetaxel vs ADT + docetaxel.

Other opportunities for early use include Lu-177-PSMA treatment for those in the following settings:

• active surveillance
• persistent PSA after prostatectomy
• salvage treatment after first recurrence
• salvage treatment after second recurrence
• metastatic CRPC before docetaxel or advanced hormonal therapies
• non-metastastic (on bone scan/CT) CRPC before docetaxel or advanced hormonal therapies

Centers in Germany may be willing to treat patients per protocol (i.e., outside of a clinical trial) in some of those situations.

Repopulation

In radiobiology, one of the ways in which radiation can fail to destroy cancer is called repopulation. It means that when radiation kills some cancer cells but leaves many behind, the remaining ones now have access to space in which to expand and access to nutrients and oxygen that the other cancer cells had deprived them of. Paradoxically, the tumor can then grow faster than it ever would have before the treatment. This is sometimes seen with rapidly growing tumors, as some head and neck cancers. They sometimes irradiate those cancers multiple times a day to prevent repopulation.

Repopulation is never seen with X-ray (or proton) treatment of relatively slow-growing prostate cancers. X-rays penetrate throughout the prostate and kill all the cancer there. If there is any survival of an oxygen-deprived tumor core, it will be killed by the next fraction of X-rays in a day or two. However, Lu-177 emits beta rays that may only penetrate to about 125 cells around each target. Ac-225 (also sometimes used in PSMA therapy) only kills about 8 cells around each target. With such short-range killing, there is a real danger of repopulation if there are insufficient PSMA targets within the tumor. Multiple treatments are usually not given for several weeks, and the tumors may have changed by then.

PSMA heterogeneity

What we have learned recently is that not only does PSMA expression change over time, but in a given patient, some tumors may express PSMA and some may not. Moreover, even within a single tumor, some cells may express PSMA and some may not.

Paschalis et al. looked at the degree of PSMA expression of 60 patients with metastatic castration-resistant prostate cancer (mCRPC). They also looked at tissue samples of 38 of them taken when they were diagnosed with hormone-sensitive prostate cancer (HSPC). To detect the amount of PSMA expressed, they used an antibody stain that attaches to the part of the PSMA protein that lies above the cellular membrane. They rated the tumors "0" if there was no PSMA up to "300" if all cells expressed PSMA. They also performed a genomic analysis, looking for mutations in over 100 genes associated with DNA-repair defects.

Among the tumor samples from men with HSPC they found:

• 42% of the 38 men with HSPC  had no PSMA at diagnosis - it only emerged later
• 5 of the 6 HSPC men diagnosed with Gleason score 6 or 7 had little or no PSMA expression at that time
• About half of 30 HSPC men diagnosed with Gleason score 8-10 had little or no PSMA expression at that time
• Those who expressed PSMA had a worse prognosis
• Expression of PSMA varied greatly (heterogeneous) between patients
• Expression of PSMA varied greatly between biopsy samples from the same patient
• The higher the PSMA expression in a patient, the greater the amount of PSMA heterogeneity

Among the tumor samples from the 60 men with mCRPC they found:

• PSMA expression had increased from when they were diagnosed with HSPC
• Half of the tumors with no PSMA at HSPC diagnosis continued to have no PSMA
• 73% expressed PSMA; 27% did not - only 1 of whom had neuroendocrine prostate cancer
• 84% of those expressing PSMA exhibited marked PSMA heterogeneity
• Heterogeneous patterns were identified:

• PSMA positive and negative cells interspersed in a single area
• PSMA-positive islands in a sea of PSMA-negative cells
• PSMA-positive regions separated by >2 mm from PSMA-negative regions
• Some metastases wholly PSMA-positive, some wholly PSMA-negative in the same patient

• Bone and lymph node metastases had similar PSMA expression; liver metastases (none neuroendocrine) had lower PSMA expression

Analysis of DNA-repair defects revealed:

• mCRPC patients with DNA-repair defects had higher PSMA expression
• HSPC patients without DNA-repair defects were less likely to become PSMA-positive
• Patients treated with PARP inhibitors were more likely to respond if they were PSMA-positive
• For validation, in a separate sample of tumors, those with DNA-repair defects were found to have much higher PSMA expression than those without such defects. This was especially true for somatic mutations in BRCA2, ATM, and dMMR.
• PSMA was downregulated in androgen-independent basal cancer cells (resistant to advanced anti-androgens) and neuroendocrine cells.

The significance of this study is that it may explain why about a third of PSMA-avid patients do not respond to Lu-177-PSMA therapy. The emitted beta particles may kill cells within about 125 cells from where they are attached at the PSMA site. Thus cells that do not express PSMA that are more than 2 mm from a PSMA-avid site will not be killed (see "Repopulation" above).

The authors hypothesize that DNA-damage repair defects cause PSMA to proliferate. If they are right, a PARP inhibitor (like olaparib), which has also been found to be effective when there are DNA-repair defects (see this link), may be able to increase the efficacy of PSMA treatment. This is the subject of an ongoing clinical trial.

(update 2/24/23) Sayar et al. report the results of a PSMA autopsy study.

• 25% had no detectable PSMA
• 44% had heterogeneous PSMA expression in multiple metastases
• 63% had at least one PSMA-negative metastasis
• Loss of PSMA expression was linked to epigenetic changes on the FOLH1 gene
• Treatment of cells (in vivo and in vitro) with HDAC inhibitors restored PSMA expression
  

HDAC inhibitors are available off-label and include: Valproic Acid (Depakote), Zolinza (vorinostat), Beleotaq (belinostat), Faridak (panobinostat), and Buphenyl (phenylbutyrate).

Practical detection of heterogeneity/ clinical trials

Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity without doing a biopsy of every single metastatic site. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan.

It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap - "discordant." On the other hand, where there is a high degree of overlap between FDG and PSMA - "concordant" - the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites.  Thang et al. reported on the survival of 30 patients who were treated with Lu-177-PSMA (who were either high PSMA/low FDG or concordant, compared to 16 patients who were excluded based on lack of PSMA (8 patients) or a high degree of discordant sites (8 patients). All patients were heavily pretreated.

• Treated patients survived 13.3 months (median)
• Untreated patients survived 2.5 months (median)

(update 12/2020) Michalski et al. looked at 54 patients. Some had at least one tumor that was positive on FDG, but negative on PSMA (FDG+/ PSMA-). They compared outcomes to patients that had only PSMA+ tumors. They found:

• A third of patients had at least one FDG+/PSMA- tumor
• Overall survival was FDG+/PSMA- patients was 6 months
• Overall survival for PSMA+only patients was 16 months

(update 2/16/22) A secondary analysis of the TheraP trial of Jevtana vs LuPSMA looked at patient response depending on whether their cancer showed up also on FDG PET scans. They looked at the percent of men whose PSA reduced by 50% or more (PSA50) in the cohort that received cabazitaxel vs the cohort that received Lu177PSMA. Each cohort was analyzed according to whether they were highly avid on a PSMA PET scan (SUVmean≥10) "high PSMA" and whether their metabolic tumor volume on an FDG scan was greater than 200ml (MTV≥200) "high FDG". They required high PSMA (SUVmax≥20), and excluded men who were FDG+ and PSMA-.

• In men with high PSMA, the PSA50 was 91% for Lu177PSMA vs 47% for cabazitaxel
• Among men with high PSMA, the odds ratio of responding to Lu177PSMA was 12.2 vs 2.2 for cabazitaxel 
• In men with low PSMA, the PSA50 was 52% for Lu177PSMA vs 32% for cabazitaxel
• In men with high FDG, the PSA50 was 57% for Lu177PSMA vs 20% for cabazitaxel
• Among men with a high FDG, the odds ratio of any response to either treatment was 0.44
• In men with low FDG, the PSA50 was 70% for Lu177PSMA vs 44% for cabazitaxel

It is unknown whether the survival of untreated patients might be longer or shorter had they received treatment. It is possible that discordant patients may benefit from sequenced (before or after) or concomitant treatment with:

• chemotherapy- 
• for non-discordant, newly diagnosed, with high-volume metastases in Australia
• for patients who have progressed after an advanced hormonal and docetaxel, this Australian trial combines it with cabazitaxel.
• immunotherapy: 
•  trials of adjuvant Keytruda in UCSF and Melbourne
•  trial of combo with Keytruda and Yervoy in Australia
•  trials of a bispecific PSMA/ T cell-recruiting antibody (BiTE) in: 
1. Los Angeles, Europe & Australia (AMG 160) (early results)
2. AMG 160 + Xtandi/Zytiga + PD1i
3. City of Hope, LA AMG 509
4.  NY (REGN5678) -> trial ended for toxicity
5. Germany AMG 212 (CD3/CC1) (Phase 1 results)
6. various US sites (HPN 424) (early results) -> trial ended
7.  various sites in N. America (JNJ 63898081)
8. TNB-585 (5 US sites)
9. CB-307 (UK)
10. LAVA1207 (4 US sites)
11. JNJ-80038114 (Nashville, France, Germany, UK)
• trial of a CAR-T/PSMA therapy at UOP, Thomas Jefferson U & Columbia and Shanghai and City of Hope
• Phase 2 trial (completed) of Progenics' antibody-drug conjugate  (PSMA ADC 2301)
• Xofigo for bone metastases - trial of a therapy that may include both
• With EBRT to oligomets in recurrent patients in Australia
• PARP inhibition - trial in Melbourne
• Enzalutamide (Xtandi) randomized trial in Australia
• Adding a systemic radiosensitizer: Veyonda (idronoxil) suppository. A phase I/II trial  found it was safe, with only anal inflammation attributable to the suppository. Results were no better than trials without the radiosensitizer; however, unlike those other trials, almost all (91%) patients had already received Jevtana.
• other novel non-PSMA targeted treatments

It is possible that such adjuvant treatment may decrease the population of discordant sites, and minimize repopulation effects.

Based on this new knowledge, it is recommended that patients who are good candidates for Lu-177-PSMA therapy have both a PSMA PET/CT scan and an FDG PET/CT at around the same time. FDG PET scans are generally covered by insurance; PSMA PET scans are not covered by insurance yet.

Optimal chemohormonal sequencing for mCRPC MAY be Taxotere->Zytiga->[Pluvicto] ->Jevtana->Xtandi

(1) Taxotere (docetaxel) first

In a retrospective study presented at the Society for Urologic Oncology meeting,  researchers at the Mayo Clinic reported on 112 patients with metastatic castration-resistant prostate cancer (mCRPC).

• Group A (80 men) had docetaxel (Taxotere) followed by one of the second-line hormonal therapies: either abiraterone (Zytiga) or enzalutamide (Xtandi)
• Group B (32 men) had a second-line hormonal therapy followed by Taxotere.
• Bone metastases were more common in Group B (87%) than Group A (58%)

Three-year survival was:

• cancer-specific survival: 87% Group A vs 64% Group B
• overall survival: 82% Group A vs 61% Group B
• results were similar for men with high volume metastases, excluding those with lymph node-only

This was not a prospective randomized clinical trial. It reaches a different conclusion from a couple of earlier retrospective analyses.  Sonpavde et al.  reported an analysis of 1445 patients at VA hospitals. They found no difference in overall survival among those who started with taxanes vs. those that started with a second-line hormonal therapy. In a study at Johns Hopkins, Maughan et al. reported that there were no statistically significant differences in total progression-free survival related to the order in which the medicines (Taxotere or Zytiga) were given. Both studies adjusted for disease characteristics.

In the STAMPEDE trial of newly diagnosed men with metastatic hormone-sensitive prostate cancer (mHSPC), there was no difference in survival among men who were randomized to get Taxotere or Zytiga first (see this link). The difference in the Mayo study may be due to "selection bias" in the retrospective study - Group A may have received Taxotere first because they were healthier, and more likely to survive.

But even if the survival difference is an artifact of the study methodology, there are other reasons to do Taxotere first:

• Side effects are less when chemo is given earlier
• In fact, side effects are no worse for chemo or Zytiga (see this link). The differences are in the kinds of side effects, but not in their seriousness.
• By starting with 6 infusions of Taxotere, one is able to use Zytiga after only 15 weeks; but if one starts with Zytiga, it may be 3 years before Taxotere can be tried (see this link).

There doesn't seem to be any cross-resistance between taxanes and Zytiga (as there is between Zytiga and Xtandi). A pilot trial combined the two without finding excessive toxicity, and larger trials of the combination are ongoing; for example, this one. However, a randomized trial of docetaxel+Xtandi vs docetaxel alone found there was no survival advantage to combining them, but toxicity was higher with the combination.

(2) Zytiga (abiraterone) before Xtandi (enzalutamide)

Khalaf et al reported the results of a randomized Phase 2 trial in British Columbia. 202 newly diagnosed mCRPC men were randomized to either Zytiga or Xtandi first. After progressing on the first therapy, they were given the second therapy (cross-over).

• The Zytiga-first men progressed after 19 months vs 15 months in the Xtandi-first group
• After cross-over, PSA was reduced by more than 30% in 36% of those who had Xtandi-second vs only in 4% of those who had Zytiga-second

Until we have a larger study that follows men for the rest of their lives, we can assume that the extended progression-free time among those who use Zytiga before Xtandi will translate to extended survival.

It's worth noting that it has been found that Zytiga can work a median of 10 months longer if one switches from prednisone (10 mg/day) to dexamethasone (0.5 mg/day) when progression begins (see this link).

A trial combining Zytiga and Xtandi (+ADT) found there was no benefit to combining the two drugs, but toxicity was worse than Xtandi (+ADT) alone. A small trial of Zytiga monotherapy (without ADT) showed that it can reduce testosterone on its own and another small trial suggested that oncological outcomes were not compromised by the monotherapy.

(Update 2/9/21) A trial combining Zytiga and Erleada (+ADT) found there was a benefit in radiographic progression-free survival (rPFS) to combining the two drugs. rPFS was extended 6 months (from 17 mos. to 23 mos.) by the combination compared to Zytiga (+ADT) alone. With median follow-up of 55 months, there was no significant difference in overall survival. Unlike Xtandi, Erleada reduces androgen receptor expression.

(Update  2/21/21) Tagawa et al. reported that in a retrospective analysis of chemo-naive patients treated at the VA, Xtandi-first patients had a 16% reduced risk of death vs Zytiga-first patients - 1.4 months longer. But if they later switched to the other drug, their overall survival was the same. There was also no difference in survival if they later had chemo.

(3) Jevtana (cabazitaxel) third (after Pluvicto)

Jevtana is currently FDA-approved for men in whom Taxotere has already been tried and failed. Jevtana and Taxotere (both taxanes) have been found to be virtually identical in oncological results when given as first-line therapy (see this link) with a similar degree of toxicity. If Taxotere and one of the second-line hormonal therapies (Zytiga or Xtandi) have already been tried, is it better to try the other second-line hormonal therapy next or is Jevtana a better choice for the third therapy? De Wit et al. found the answer in the CARD randomized clinical trial..

They randomized patients who already had Taxotere and one of the two second-line hormonal to receive either the other second-line hormonal or Jevtana.

• 126 received Jevtana
• 58 received Zytiga
• 66 received Xtandi

After 9.2 months median follow-up, 

• Imaging-based progression-free survival was 8.0 months for Jevtana vs 3.7 months for the hormonal therapy
• The advantage for Jevtana was maintained regardless of risk characteristics and treatment history
• The advantage for Jevtana was true regardless of which hormonal therapy it was compared to.
• Overall survival was 13.6 months for Jevtana vs 11.0 months for hormonals.
• PSA was reduced by at least 50% in 36% of men using Jevtana vs 14% using hormonals.
• Tumors shrank in 37% of men using Jevtana vs 12% using hormonals
• Serious adverse events of any grade were similar for all therapies at 39%.
• Adverse events leading to death were more frequent with the hormonals (11%) than Jevtana (6%)
• Pain was improved more by Jevtana (in 45% of men) than by hormonals (in 19% of men)
• Skeletal events (fractures, spinal compression) occurred more frequently among those taking hormonals (51%) than Jevtana (29%)

Jevtana was at least as good or had a clear advantage on every measure of success.

(Update 9/16/20) Fizazi et al. reported the Quality of Life (QOL) outcomes of the CARD trial (above).

• Pain response was better with Jevtana  than hormonals (46% vs 19%)
• Time to pain progression was about twice as long with Jevtana (hazard ratio (HR)= 0.55)
• Time to next symptomatic skeletal event was similarly longer with Jevtana (HR= 0.59)
• Function scores and time to deterioration of function scores (e.g., ability to self-care, perform usual activities, mobility, mental status, sense of well-being, social/family well-being) were better with Jevtana

(4) Xtandi fourth

There is some evidence that taxanes (like Taxotere or Jevtana) can reverse one mode of hormonal resistance (AR-V7 splice variance). More evidence proved that Taxotere combined with Xtandi can extend its effectiveness even after it fails. Research continues on methods to reverse resistance (e.g., see subsection - "what's next?"). Although there is known cross-resistance between Zytiga and Xtandi, Xtandi usually works at least for a while after Zytiga.

Other medicines

Other medicines approved for men with mCRPC include older anti-androgens (like bicalutamide), Xofigo, Provenge, and Keytruda (but only in the rare event of MSI-hi/dMMR). It would save time if any of these could safely be piggybacked on top of another therapy.

Older anti-androgens (like Casodex or flutamide) are still used sometimes in the mCRPC setting, mostly in combination with a GnRH agonist (like Lupron). The combination is somewhat more beneficial (see this link) than a GnRH agonist alone, and provides a short-term benefit at low cost. Sometimes, the cancer learns how to feed on the anti-androgen, and removing it leads to a reduction in PSA (called antiandrogen withdrawal syndrome). Newer antiandrogens don't seem to do this as much, although it has been observed in a minority of patients for abiraterone and enzalutamide.

It is unknown where the newest antiandrogens fit into sequencing. Erleada and Nubeqa have been approved for other indications, but not yet for mCRPC. Others (like proxalutamide) haven't yet cleared the first hurdle.

Xofigo cannot be prescribed after any visceral metastases have been detected, although it may work well on the bone metastases nevertheless. It works better sooner rather than later, but a trial combining it with Zytiga was stopped early because of a high rate of skeletal events. Early results of a new trial combining Xofigo and Xtandi show that adding a bone-protective agent (Xgeva or Zometa)  can ameliorate the problem.

Provenge may synergize with radiotherapies or chemo because they present many cancer antigens for the amped up immune system to tune into. There is some evidence to suggest that it synergizes with Xofigo. There is evidence that an abscopal effect (systemic immune response) may be augmented. Other immunotherapies, which show little therapeutic promise alone, may be beneficial in combination with chemo or other therapies.

PARP inhibitors are in clinical trials, and seem to be especially effective when there are BRCA1/2 mutations (germline or somatic). Several clinical trials are combing carboplatin with taxanes. Transdermal estrogen is inexpensive and is available now. Optimal sequencing or combinations are yet to be determined. 

Lu-177-PSMA-617 ("Pluvicto") and similar radiopharmaceuticals are in ongoing trials. (Update: see this link.) The TheraP trial proved that Pluvicto is preferred as a third treatment over jevtana. The VISION trial used it only among men who had been pre-treated with chemo and Zytiga or Xtandi. If it gets FDA approval, it will be limited to use after those other treatments. However, trials are ongoing for earlier use and in combination therapy. There is probably an optimum time for use of PSMA-directed therapies. Combination with different PSMA-targeted radionuclides (like Ac-225), and with multiple membrane targets are being explored.

There are myriad other potential therapies in clinical trials. Many are pathway growth inhibitors that may work best in combinations. Therapies tailored to specific genomic mutations are in their infancy.

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.

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.