Showing posts with label mCRPC. Show all posts
Showing posts with label mCRPC. Show all posts

Friday, January 27, 2017

I-131-MIP-1095, a new radiopharmaceutical, in clinical trials at Memorial Sloan Kettering

There are few radiopharmaceuticals in clinical trials in the US (there are several in use in Germany), so when a new one is announced, we take notice. I-131-MIP-1095 has had a very limited clinical trial in Germany in 28 patients, and will now be tried in the US.

Like Lutetium 177, Iodine 131 is a beta particle emitter (see this link). It's beta particle energy is somewhat higher, so that it can penetrate greater distances through tissue - up to 3.6 mm, compared to 1.9 mm for Lu-177. This is an advantage in that it can destroy larger tumors, but it is a disadvantage in that it may destroy more healthy tissue, causing hematological and renal side effects. It is also similar to Lu-177 in that its uptake in human tissues can be detected using a gamma ray camera or SPECT detector. Because gamma ray detection does not afford the image quality that PET/CT does, it may be combined with a positron emitter, I-124. Lu-177 is sometimes combined with Ga-68 for the same purpose. This combination of therapeutic and diagnostic (sometimes called theranostic) may be useful in tailoring the dose to the patient based on individual uptake characteristics.

The molecule (or ligand) that the I-131 is attached to is MIP-1095. MIP-1095 is attracted to the PSMA protein on the surface of 95% of prostate cancer cells. Although it is highly specific for prostate cancer, there are other tissues that express PSMA, especially the salivary glands and lacrimal glands. It is excreted by the liver and kidneys, and may show up in the intestines, and the lower urinary tract. The dose to the kidneys may limit the amount of the pharmaceutical that may be given to the patient.

A group from the University Hospital Heidelberg, Zechman et al., treated 28 metastatic castration-resistant patients with I-131-MIP-1095 with the following results:

  • In 61%, PSA was reduced by >50%. This is better than the response seen with Lu-177-PSMA-617 in these trials and in this one.
  • PSA decreased in 21 of 25 patients, increased in 4.
  • 85% had complete or moderate reduction of bone pain. 
  • 25% had a transient slight to moderate dry mouth, which resolved in 3-4 weeks.
  • White blood cell count, red blood cell count and platelets declined during treatment, but there were only 3 cases of grade 3 hematologic toxicity, often in patients with low blood counts at baseline.
  • No renal toxicity was observed.
  • The effective dose to cancer cells was higher than for Lu-177-PSMA-617, red marrow and kidney doses were similar, and liver dose was lower.

The clinical trial that is now recruiting at Memorial Sloan Kettering, is a Phase 1 trial to find the best dose of I-131-MIP-1095 among patients with metastatic castration-resistant prostate cancer. Doses will be administered 12 weeks apart for up to 5 cycles or until dose-limiting toxicity is observed (monthly assessments). Interested patients in the New York City metropolitan area should call the contacts listed on the bottom of this trial description.

Saturday, December 31, 2016

Ipilimumab (Yervoy) fails to increase survival, even when used earlier

Ipilimumab (Yervoy) is a type of immunotherapy that is known as a "checkpoint blocker." It blocks a protein in T-cells (called CTLA-4) that tells the immune system to stand down and not attack the cancer cells. It turns off the off-switch. The hope is that immune response against the cancer will continue longer than it ordinarily would.

A previous trial showed that Yervoy did not extend survival when used in men who were metastatic and castration-resistant  (mCRPC) and who had failed chemotherapy. This is often the first group given a new drug because other options have been exhausted and because it takes less time to prove efficacy. Researchers hoped that it might have some effect if used earlier in disease progression. Unfortunately, it did not.

Beer et al. tested Yervoy this time in men who were metastatic and castration-resistant but who had not yet tried chemotherapy and who were asymptomatic or minimally symptomatic (i.e., no bone pain or organ dysfunction). In this multi-institutional study, there were 399 patients who got Yervoy, and 199 who got a placebo. Neither patients nor doctors knew who got which.
  • Patients were given 10 mg/kg of Yervoy or placebo every 3 weeks for up to 4 doses.
  • Therapy was repeated every 3 months thereafter to non-progressing patients
The outcomes were as follows:
  • Median overall survival was 28.7 months for those who got Yervoy vs. 29.7 months for those who got the placebo (no statistically significant difference).
  • Median progression-free survival was 5.6 months or those who got Yervoy vs. 3.8 months for those who got the placebo (a statistically significant difference).
  • 23% had a PSA response with Yervoy vs. 8% with the placebo.
The treatment-related adverse responses were:
  • Death that was treatment-related in 9 patients (2%).
  • Serious or life-threatening immune-related adverse events in 31%
  • Serious or life-threatening diarrhea in 15%
While there was a PSA  response, and an increased time during which more patients taking Yervoy were progression free, this did not translate to a lengthening of overall survival. This may be because there was a subset of patients who had a good initial response, but the response was not sustained. This also shows the difficulty of measuring the response to immunotherapy using PSA or other surrogate endpoint. We know that Provenge, the only approved immunotherapy for prostate cancer, lengthens survival without reducing PSA. Here, the converse is true.

Research continues on other checkpoint blockers. Keytruda has been approved for melanoma, lung cancer and head-and-neck cancer. In addition to Keytruda, there are several investigational immunotherapies targeting the PD-1/PD-L1 antigen. It may turn out that checkpoint blockers work better in combination with other immunotherapies (like Provenge or ProstVac), or perhaps they need to be primed with concurrent SBRT radiotherapy or chemotherapy. We need a better understanding about why an immunotherapy may work very well for one cancer, but very poorly for another cancer, We also can't lose sight of the fact that all  immunotherapies may be lethal. There is clearly much to be learned.

Sunday, September 4, 2016

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mCRPC)


When prostate cancer metastasizes and becomes castration-resistant (mCRPC) after a period of androgen deprivation therapy (ADT), a number of biochemical changes to the androgen receptor (AR) take place within the cancer cell. Among those changes:
  • The androgen receptor (AR) multiplies on the cancer cell surface so that even the smallest amount of testosterone or other circulating androgens can activate it.
  • Even without an androgen ligand, the androgen receptor moves from the surface of the cell to the inside where it is protected. These internalized androgen receptors play a role in encouraging cell replication and in self-destruction (apoptosis) of cells in which the DNA  has become irreparably damaged.
  • The cell manufactures its own androgens internally. These activate the internalized androgen receptors.
  • The androgen receptor mutates into truncated versions that can be activated by a host of other molecules (other than testosterone), or don't require other molecules at all to activate it. Recently, researchers at Johns Hopkins identified a version called the "AR-V7 splice variant" that allows the cancer cell to multiply even when all androgens are completely eliminated. It is induced by long term androgen deprivation (see this link).
There may also be tissue-based effects. This means that, in a tumor, there are a variety of cell types. Castration resistance is not an all-or-none situation. Some cells within any given tumor will always remain hormone sensitive. Some cells, like cancer stem cells, have never been hormone sensitive. All of these cell types interact. Hormone-sensitive cells signal castration-resistant cells to become more like them. At the same time, castration-resistant cells signal hormone-sensitive cells to become more like them. Over time, the hormone-sensitive cells (being the ones that are killed by ADT)  lose the battle as the equilibrium shifts towards castration resistance.

How testosterone can help

Supraphysiologic doses, meaning serum levels greater than 1000 ng/dL, may help in several ways:
  • Testosterone prevents the androgen receptor from multiplying on the cell surface, and decreases the  number of androgen receptors already there, thereby increasing the cancer cell's sensitivity to subsequent androgen ablation (see this link). It also prevents the cell from becoming super-sensitized to androgens.
  • Inside the cell, high levels of testosterone prevent the internalized androgen receptors from encouraging cell replication - too much testosterone, as well as too little testosterone discourages cancer cell replication (see this link).
  • High levels of testosterone and other androgens may induce damage the cancer cell's DNA (see this link). One of the interesting hypotheses is that combining high testosterone with a chemotherapy that is known to cause DNA damage will be particularly effective (see below).
  • Testosterone may be able to reverse the AR-V7 splice variant that is known to cause resistance to even second-line hormonal therapies like Zytiga and Xtandi (see this link).
  • On the tumor tissue level, testosterone supports the growth of hormone-sensitive cells while destroying castration-resistant cells, as described. This shifts the equilibrium back towards androgen deprivation sensitivity.

Why can't we just give continuous high doses of testosterone?

It's been known for a while that testosterone plays a role in keeping healthy prostate cells healthy. We have observed that hypogonadal men (men who have low natural levels of testosterone) are more likely to have prostate cancer, and more virulent types. For a thorough recent review of this subject, see this link. In fact, one pilot study showed that men with mCRPC who had higher plasma testosterone levels (but still at castration levels) survived twice as long. They responded better  to chemotherapy as well (see this link).

In 2009, Robert Liebowitz et al. reported on 96 patients who received very high dose testosterone replacement therapy (TRT) after some kind of prostate cancer treatment. For 59 of those men, the only treatment had been androgen deprivation. 12% were detectably metastatic. 60% had PSA progression while on TRT, but few had metastatic progression in that time period. For most of those, discontinuing TRT reversed the PSA progression.

There was a small (12 man) safety trial at Memorial Sloan Kettering. None of the men achieved supraphysiological serum testosterone levels from the transdermal gel they used. One man had to discontinue when he experienced spinal pain, but there weren't any other major side effects. Of the 12 men, 7 had decreased PSA (one had a 50% decrease). The other 5 had increased PSA, 2 by more than 50%. There was no regression of metastases in any of the men.

Other small trials of TRT alone had mixed results (see this link and this one).

So TRT alone doesn't seem to work. Both effects are necessary: (1) the TRT re-establishes hormone sensitivity, and then (2) the ADT kills off the hormone-sensitive cancer cells. For disease stabilization or regression, it seems to be necessary to alternate TRT with ADT. This is called bipolar androgen therapy (BAT).

I'm on intermittent hormone therapy - doesn't that accomplish the same thing?

Unfortunately, no. It had been hoped that intermittent ADT would accomplish two benefits:
  1. Delay the development of castration resistance, and thereby prolong survival, and
  2. Give men a break during which quality of life would improve temporarily
In fact, it accomplishes neither for most men, although it may for some. At least we know that intermittent ADT is not usually inferior to continuous androgen ablation, although it may be for some (perhaps those with multiple metastases, especially). We are beginning to understand why it usually does not accomplish those twin goals.

After a long while on ADT, it takes a long time for a man's testicles to recover the ability to generate amounts of testosterone that are adequate to recover libido and help a man feel better. As far as the cancer is concerned, the cancer couldn't adapt if it were suddenly shocked by a large surge of testosterone. But during the "off-cycle,"as the amount of testosterone slowly increases, his cancer is able to adapt.  The cancer consequently thrives on the incremental increases rather than being killed by it. By the time the testosterone reaches a level that makes a measurable difference to his quality of life, the cancer has proliferated. His PSA has then gotten so high that the ADT "holiday" must be ended.

It sounds good in theory, but does it work in clinical practice?

Schweizer et al. conducted a pilot test at Johns Hopkins. They treated 16 asymptomatic men who were diagnosed a metastatic and castration-resistant. They were all still on ADT. They gave the men high doses of injected testosterone and treatment with the chemo drug etoposide (see above), which is normally ineffective in treating prostate cancer. After at least 3 cycles:
  • Half of them enjoyed a decline in PSA, most of those by more than a 50% decline
  • Half had a radiographic response, including 1 patient who had no discernable metastases
  • Half the patients did not respond at all, and PSA continued to rise
  • Responders had a higher pre-BAT PSA than non-responders
  • 10 of 10 patients (100%) responded to second-line ADT (Xtandi, Zytiga or Casodex) after BAT (some were resistant to those therapies before BAT)
  • 3 patients had severe toxicity attributable to etoposide.
It appears that BAT may at least delay progression in men with mCRPC. It seems to resensitize their cancers to hormonal agents, even when it didn't succeed in decreasing PSA or evident (radiographic) progression. We don't yet know if it increases survival. Importantly, the men periodically enjoyed enhanced quality of life from periodic high levels of testosterone. It's unclear whether etoposide chemotherapy added much to the response.

What's next?

In their next clinical trial, the researchers are investigating whether BAT can restore sensitivity to Zytiga and Xtandi to mCRPC men who have already progressed while using those. They are excluding those who have already had chemotherapy, and no chemo is used in this trial. (Update July 2020) The RESTORE trial found that BAT was able to restore responsiveness to Xtandi but much less to Zytiga.
  • After BAT, PSA declined by ≥50% in 68% on rechallenge with Xtandi
  • After BAT, PSA declined by ≥50% in 16% on rechallenge with Zytiga
(Update 6/2017) Denmeade's group reported on 30 minimally symptomatic mCRPC men who had progressed on Xtandi.
  • 30% saw PSA reduced by at least 50%
  • 43% saw PSA increase from baseline; in 17%, PSA more than doubled.
  • 36% had some regression of disease
  • Median 8.6 months of radiographic/clinical progression-free survival
  • 54% responded to re-challenge with Xtandi with a subsequent drop in PSA by at least 50% and progression-free survival of 4.8 months
  • A third of those with the resistant AR-V7 mutation responded to BAT, and had lowered AR-V7 levels
  • 2 converted from AR-V7 positive to AR-V7 negative
There were adverse side effects while on BAT. Transient pain flares was the most common, affecting 40%. A few men suffered very serious side effects: pulmonary embolism, heart attack, urinary obstruction, gallstones and fatal sepsis.

In a second clinical trial, chemo-naive mCRPC men who have failed therapy with Zytiga will be randomized to receive either BAT or Xtandi. This trial will be re-opened in July 2020.

In another clinical trial, men who are mCRPC and who have progressed on either Zytiga or Xtandi, will receive BAT and Nivolumab (an immune checkpoint inhibitor).

(Update 11/8/18) A new clinical trial at the University of Colorado, Denver will try transdermal testosterone instead of injections alternating with enzalutamide.

It will be important to determine, in future clinical trials, which men will respond to BAT and which men will not. It is also not yet clear if there is a survival benefit, although there is a quality of life benefit. Importantly, all clinical studies so far have only been pilot trials in very small groups of patients. Larger trials will be necessary to prove safety and efficacy. These determinations should only be made as part of a careful clinical trial.

There may be particular situations where BAT may be an effective therapy, but data are so far lacking: 
  • What, if any, is its benefit in men who are metastatic but still hormone responsive (mHSPC)? 
  • Does it have any benefit in men who have already had docetaxel chemotherapy? 
  • Considering that metastases shrank in many men on BAT, should it be tried in symptomatic men as well? 
  • What is its effect on AR-V7-positive or negative men? 
  • Should it be used in combination with other therapies, such as PARP1 inhibitors, immunotherapies, and radiological therapies? 
  • What is the optimal sequencing of therapies? 
  • Is there any benefit to BAT  used along with radiation therapy in high risk men (see this link)?