Thursday, December 19, 2019

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.

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:

Sunday, December 15, 2019

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


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.


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:
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.

Saturday, December 7, 2019

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.

Tuesday, October 1, 2019

PARP inhibitors slow progression and increases survival in men with BRCA gene mutations

The PROfound Trial has reported (here) significant improvements in progression-free survival in men with BRCA2, BRCA1, and ATM gene mutations who took the PARP inhibitor, olaparib (Lynparza). BRCA2, BRCA1, and ATM germline gene mutations are found in about 8% of men with metastatic castration-resistant prostate cancer (mCRPC). The study also included men in whom those genes were mutated in their tumors (called "somatic" mutations). PARP inhibitors inhibit an enzyme that supports the survival of DNA-damaged cancer cells. Lynparza is FDA-approved for ovarian cancer and breast cancer. Other FDA-approved PARP inhibitors comprise Rubraca (rucaparib) and Zejula (niraparib) for ovarian cancer, and Talzena (talaparib) for breast cancer. They are all in clinical trials for prostate cancer (see this link).

The PROfound Trial (details here) compared the effectiveness of Lynparza to either Xtandi or Zytiga (cohort B) in men who had already failed one of them. They compared the two groups in men who had somatic mutations in BRCA 1/2 or ATM (Cohort A, n=245) and in men who had somatic mutations in any of 12 other DNA-repair genes (Cohort B, n=142), and in men who had any of the 15 DNA-repair mutations (Cohort A+B, n=387). The trial was conducted at 229 sites. The 12 other DNA-repair mutated genes were BARD1, BRIP1, CDK12, CHK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L.

Their interim (median 1 year) findings comparing Lynparza vs Xtandi/Zytiga were as follows:

Median radiographic progression-free survival (rPFS):
  • Cohort A: 7.4 months vs 3.6 months (HR=0.34, p<0.0001)
  • Cohort A+B: 5.8 months vs 3.5 months (HR=0.49, p<0.0001)
Among the combined cohorts (A+B):
  • 6-month rPFS: 60% vs 23%
  • 12-month rPFS: 28% vs 9%
  • Objective Response Rate: 33% vs 2%
  • Time to pain progression: not reached vs 10 months
Median overall survival (OS) (updated 9/22/20 ):
  • Cohort A: 19.1 months vs 14.7 months (HR=0.69, p=0.02)
  • Cohort A+B: 17.3 months vs 14.0 months (not statistically significant)
  • Cohort B: 14.1 months vs 11.5 months (not statistically significant)
  • Two-thirds of controls crossed-over to receive olaparib
  • After adjusting for cross-over, the hazard ratio improved to 0.42 in Cohort A, but were not significant in Cohort B or Cohort A+B
Adverse Events:
  • Lynparza patients had more anemia, nausea, fatigue & asthenia, decreased appetite, diarrhea/constipation, vomiting, and respiratory issues.
  • 16.4% discontinued with Lynparza vs 8.5% discontinued with hormonal therapy
  • Nevertheless, they stuck with Lynparza for 7.4 months  vs 3.9 months with hormonal therapy
(update 5/19/20) The FDA approved Lynparza for mCRPC patients with germline or somatic homologous recombination repair mutations who have progressed on Zytiga or Xtandi.

In a small study (12 BRCA1/2-mutant, 5 ATM-mutant), Marshall et al. reported activity in men with BRCA1/2 mutations, but not ATM mutations:

  • Reduction of PSA by at least 50% was seen in 83% of men with BRCA1/2 mutations vs 0% of men with ATM mutations.
  • Progression-free survival was 12.3 months in men with BRCA1/2 mutations vs 3.3 months in men with ATM mutations.

Similarly good responses among men with bi-allelic (both genes mutated) BRCA1/2 mutations vs other DNA-repair mutations were reported in a Phase 2 trial of niraparib. The FDA has granted it "breakthrough therapy" designation.

Men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see this link).

Preliminary results of the TRITON 2 clinical trial of rucaparib in men with DNA-damage repair (DDR) deficiencies (either germline or somatic) were also reported. Clinical benefit (the % who had no radiographic progression and stayed with rucaparib) at 6 months and 12 months for each of the DDR genes found were as follows:

  • BRCA1/2: 56% (47/84) at 6 mos., 25% (6/53) at 12 mos.
  • ATM: 29% (14/48) at 6 mos., 8% (2/25) at 12 mos.
  • CDK12: 21% (3/14) at 6 mos., 7% (1/14) at 12 mos.
  • CHK2: 67% (2/3) at 6 mos., 0% (0/1) at 12 mos.
  • Other DDR: 50% (6/12) at 6 mos., 33% (3/9) at 12 mos.
(update 8/23) The percent who had a reduction in PSA greater than 50%:
  • BRCA1/2: 53%
  • PALPB2: 55%
  • ATM: 3.4%
  • CDK1/2: 6.7%
  • CHEK2: 14%
  • Other DDR: 23%
There was high treatment-related toxicity in these heavily pre-treated patients:
  • Treatment interruption or dose reduction in 54%
  • Discontinuation in 9.5%
  • Most common serious (grade 3+) adverse events: anemia (18%), fatigue (11%), thrombocytopenia (6%)
  • 5 deaths (3%)
(Update 5/15/20) The FDA approved rucaparib for men who have the BRCA mutation (either germline or somatic, and have had prior taxane chemotherapy and AR-directed hormone therapy.

(Update 2/18/23) Triton 3  compared rucaparib to physician's choice of abiraterone, enzalutamide or docetaxel in 405 patients who were either BRCA+ or ATM+. After 62 months of follow-up:
  • radiographic Progression Free Survival (rPFS) was 10.2 mos. vs 6.4 mos. -- 39% improvement for rucaparib.
    • rPFS was 11.2 mos. vs 6.4 months in those who were BRCA+ (50% improvement)
    • rPFS was not significantly different for ATM+ patients
  • (update) rPFS improvement was 36% compared to docetaxel, and 53% compared to abi or enza
    • In those with BRCA+, rPFS improvement was 47% compared to docetaxel, and 62% compared to abi or enza
  • fatigue, nausea, and high BP were the most non-hematological frequent adverse events
  • anemia and neutropenia were the most serious hematological events

(Update 2/22/21) Early results of the TALAPRO-1 trial of talaparib have been presented. The 128 patients were previously treated with docetaxel, and half had cabazitaxel too. The trial only included patients with genomic DNA damage-repair (DDR) defects.
  • The overall objective response rate (ORR) was 30% 
    • 46-50% for BRCA1/2
    • 25% for PALB2
    • 12% for ATM
  • ORR took 3.4 months to be observable and lasted for 12.8 months
  • Radiographic progression-free survival (rPFS) was 5.6 months
    • 11.2 months for BRCA1/2
    • 5.6 months for PALB2
    • 3.5 months for ATM and other DDR defects
  • Most saw a reduction in tumor burden (82%), PSA (72%), and CTC (82%)
    • Reductions greatest BRCA1/2>PALB2>ATM (similar patterns in overall survival and time to PSA progression).
  • The most common treatment-emergent adverse events were anemia (49%), nausea (33%), decreased appetite (28%) and asthenia (24%).
  • Serious/life-threatening adverse events included anemia (31%), decreased platelet count (9%), neutropenia (8%), and pulmonary embolism (6%)
  • 12% discontinued treatment due to adverse events
Patients are encouraged to get the relatively inexpensive ($249) germline test, or if negative for actionable mutations, a genomic test of a tumor biopsy or of cell-free DNA (from a blood test).

Sunday, September 29, 2019

"Adjuvant" similar to "Early Salvage" Radiation Outcome in Meta-analysis

Although at least three randomized clinical trials have told us that adjuvant radiation after prostatectomy often affords better results than just taking a "wait-and-see" approach, most radiation oncologists have been reluctant to immediately treat every man with poor post-prostatectomy pathology results (positive margins, stage T3/4, high Gleason score).  Now, some early combined results (called a meta-analysis) of three more randomized clinical trials suggest that oncological outcomes will be no worse if men wait to be treated until certain PSA cut-offs are reached.

The three randomized clinical trials were RADICALS-RT (UK & Canada), GETUG-AFU-17 (France), and RAVES (Australia & NZ). The meta-analysis, called "ARTISTIC" (critique here). comprised 2151 men, of whom 1074 were randomized to adjuvant radiation and 1077 were randomized to early salvage radiation. There have been 5 years of follow-up so far. ARTISTIC analyzed the early data based on "event-free survival," which for the most part meant freedom from a PSA-defined recurrence after radiation.

"Adjuvant" radiation (ART) was defined by all three trials as treatment within 6 months of prostatectomy. Note that this can be longer than the "immediate" treatment often given.

"Early salvage" radiation (eSRT) was defined variously as treatment when PSA ≥ 0.1ng/ml or 3 consecutive rises (RADICALS-RT), PSA≥0.2 ng/ml and rising (GETUG-AFU-17), or PSA≥0.2 ng/ml (RAVES).

Patients in all three trials had positive surgical margins, extracapsular extension, or penetration into the seminal vesicles. Most patients were intermediate risk:
  • Most (77%) had a Gleason score of 7
  • Very few (9-17%) had a Gleason score of 8-10
  • About 1 in 5 had seminal vesicle invasion

After 5 years of median follow-up:
  • Event-free (mostly PSA) survival was about the same for ART and eSRT (HR=1.1, p=0.47)
  • 57% of patients randomized to SRT never had it because they didn't have biochemical progression

The following are the results for RADICALS-RT (1,496 patients followed up for 4.9 years):
  • 64% of the patients randomized to receive eSRT, never experienced PSA progression
  • At 5 years, biochemical progression-free survival was 85% for ART and 88% for eSRT (p=0.56, not statistically different)
  • At 5 years, freedom from permanent ADT was not different (93% for ART, 92% for eSRT)
  • Urinary incontinence at one year was 5.3% for ART vs 2.7% for eSRT (p=0.008, statistically different)
  • Serious or life-threatening urethral stricture was 6% for ART vs 4% for eSRT (p=0.02, statistically different)

The following are the results for GETUG-AFU-17 (424 patients with 6.3 yrs of follow-up):
  • 41% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr event-free survival (no PSA or clinical relapse) was the same (92% for ART, 90% for SRT)
  • Late-term urinary toxicity (any grade) was worse for ART (73% for ART, 29% for SRT)
    • incontinence:  54% for ART, 17% for SRT
    • frequency: 39% for ART, 15% for SRT
  • Late-term rectal toxicity (any grade) was worse for ART (44% for ART, 20% for SRT)
  • Late-term erectile dysfunction (any grade) was worse for ART (36% for ART, 13% for SRT)

The following are the results for RAVES (333 patients with 6.1 yrs of follow-up):
  • 47% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr freedom from biochemical relapse was the same (86% for ART, 87% for SRT)
  • Late-term urinary toxicity (grade 2+) was worse for ART (70% for ART, 54% for SRT)
  • Late-term rectal toxicity (grade 2+) was the same (14% for ART, 10% for SRT)

Pelvic lymph nodes

If pelvic lymph node dissection during prostatectomy revealed any positive nodes, or if scans suggest enlarged, cancerous pelvic lymph nodes, there is no question that adjuvant radiation is required. RTOG 0534 (SPPORT) showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increased progression-free survival even when there were no detected cancerous lymph nodes, but only if PSA was high enough.

It is never worth waiting for PSA to rise to a point where newer PET scans can detect metastases just to find out where the largest sites of recurrence are. That would be a self-fulfilling prophecy - the goal is curative treatment before the cancer has time to metastasize. A/SRT must be given to the prostate bed, and possibly an extended pelvic lymph node field (see this link). The patient must treat what is still too small to see.

Adjuvant ADT

RADICALS-HD explored the effect of various durations of adjuvant hormone therapy, and found that 6 months was no more beneficial than none! However,  GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 (SPPORT) also showed that adding ADT to SRT was often beneficial. But RTOG 9601 showed that adjuvant ADT did not improve results when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that metastatic risk may outweigh benefits when PSA is lower than 0.6 ng/ml. However, SPPORT found that men with a PSA above 0.35 (median, not a definitive cut-off) were more often cured if they got short-term ADT

See this link for updates on this topic.

Radiation Dose

GETUG-AFU-17 and RADICALS-RT used a radiation dose of 66 Gy in 33 treatments. RADICALS-RT also allowed a moderately hypofractionated dose (52.2 Gy in 20 treatments). RAVES used a slightly lower dose: 64 Gy in 32 treatments. SAKK 09/10 found that the salvage dose in the RAVES trial had equivalent biochemical outcomes. The effect of the higher dose on toxicity using the best linacs is unknown.

High Risk/Decipher

Most of the men in these trials were originally intermediate risk. It is entirely possible that originally high-risk men (Gleason 8-10, PSA≥20 or cT3/T4) may benefit more from ART rather than eSRT.  Men who were originally low risk (Gleason 6 and PSA<10 and T1/2) may be able to wait longer or indefinitely before SRT.

If the Decipher score is very high, that should also be taken into account in deciding between ART and eSRT. Genome Dx also provides scores that suggest whether the cancer is amenable to SRT, but those scores have yet to be prospectively validated.

We are starting to get a better handle on the ART vs eSRT decision, but none of what we have learned gives us hard-and-fast guidelines. Thee trial results do provide more fodder for discussion between the patient and his radiation oncologist.

Exceptions: see this link.

Tuesday, September 17, 2019

SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:
  • Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
  • Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
  • The time to progression was increased by 70% by the treatment.
  • Progression has not been reached among those treated patients followed for over a year.
Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:
  • PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
  • Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
  • Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.
PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:
  1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
  2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
  3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.

Thursday, August 15, 2019

The definition of SECOND biochemical recurrence (after prostatectomy AND salvage radiation)

There is no standard definition of SECOND biochemical (PSA-detected) recurrence (BCR); that is, after both prostatectomy and salvage radiation (SRT). There are two reasons to have a standard definition of second BCR:

  1. Time for next treatment: BCR (after any treatment) is the first indicator of treatment failure, and a signal that it may be time to consider additional treatment. It is not at all clear that immediate additional treatments are beneficial. If a treatment becomes the standard of care after biochemical failure, then it will be necessary to define the PSA or PSA doubling time (PSADT) at which that treatment should begin.
  2. Comparison among radiation protocols: Lacking randomized clinical trials among all the variables of when and how salvage radiation are given (pathological characteristics, PSA, PSADT, radiation dose, adjuvant ADT, prostate bed radiation, radiation of pelvic lymph nodes), we can only look at effectiveness across studies to help us hypothesize that one strategy might be better than another. It helps if we have a consistent definition of success.
Miyake et al. looked at three definitions of second BCR:
  1. NARA definition: PSA never falls below 0.2 ng/ml; or, it falls below 0.2 ng/ml but later rises over it in two consecutive readings.
  2. RTOG 9601 definition: any post-SRT PSA over 0.5 ng/ml; or, nadir + 0.3 ng/ml; or the start of hormone therapy.
  3. GETUG definition: nadir + 0.5
They evaluated 118 patients using the 3 definitions. With 49 months of median follow-up after salvage radiation:
  • The Nara definition had the highest rate of second BCR; 53%, 45% and 40% for Nara,  RTOG and GETUG respectively.
  • Gleason score and Pre-SRT PSA independently predicted Nara BCR, while negative margins and PSADT also predicted RTOG and GETUG BCR.
  • There were no discrete cut-offs of the patient characteristics that reliably predicted BCR by any definition
It's worth noting that the definitions may differ for study entry and endpoint (it is usually called "biochemical progression" when used as an endpoint). Many clinical trials use the 0.2 ng/ml definition for the second BCR too.  This trial used PSA≥ 0.2 ng/ml or 3 consecutive rises after RP or SRT. We recently saw that another RTOG trial, the SPPORT trial, used a BCR endpoint definition of nadir + 2 because it correlated well with clinical recurrence. This is the definition advocated by PCWG2.

It is sometimes necessary to define a THIRD BCR as an endpoint to determine whether a therapy that began after a second BCR was successful. For example, an ongoing trial of hormonal therapies for SRT-recurrent men uses a second BCR definition of PSA > 0.5 ng/ml and PSADT ≤ 9 months, and a third BCR definition of a confirmed 25% rise in PSA and nadir + 2 during therapy, and a fourth BCR definition of a confirmed PSA > 0.2 after hormonal therapy.

The definition for FIRST BCR of a confirmed PSA after prostatectomy of 0.2 ng/ml was an artifact of the current lowest discernible PSA before the 21st century, which was 0.1 ng/ml at the time. The American Urological Association decided that anything higher than that would be deemed a BCR. The "ARTISTIC" meta-analysis established that for most patients, it was unnecessary to establish a PSA for first BCR below 0.1 or 0.2.

BCR is just one of a number of elements to be evaluated after SRT. A BCR with a high Decipher score may suggest that immediate salvage ADT is appropriate. With the new generation of PET scans, which can detect metastases at low PSAs, it may sometimes be beneficial to treat pelvic lymph node metastases and possibly distant metastases if SRT had only included the prostate bed.

This small, retrospective study will not establish a new definition, but it does raise the interesting question of whether we need a standard definition, or whether the definition ought to depend upon the purpose for which it is used. If we have definitive evidence that early treatment after failed SRT is beneficial, that will force researchers to investigate the optimum PSA (or PSADT) cutpoint. Until then, the PCWG2 definition (PSA≥ nadir + 2.0), PCWG3 definition (PSA≥nadir+ 1.0), or the combination of PSA and PSA doubling time used in the EMBARK protocol (PSA≥1 and PSADT≤ 9 months) are all reasonable.

Thursday, August 8, 2019

PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

Detected - % of patients
Prostate bed
Pelvic lymph nodes
Extra-pelvic lesions

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)
0.2-0.5 (n=26)
0.51-1.00 (n=18)
1.01-2.00 (n=6)

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)
n = 3,217 in 38 studies
n = 482 in 6 studies

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.