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

Saturday, April 13, 2024

Pluvicto+Xtandi Delays Progression Better than Xtandi-alone in mCRPC

Both Pluvicto (177LuPSMA-617) and Xtandi (enzalutamide) have been separately shown to delay progression and extend survival among metastatic and castration-resistant men with prostate cancer (mCRPC). Because they inhibit prostate cancer in different ways, it was hoped that combining them would have an additive benefit. In a clinical trial, enzalutamide temporarily increased expression of PSMA, so a synergistic effect is possible.

Emmett et al. reported the first results of the ENZA-p trial. 162 mCRPC patients with 2 or more risk factors were treated at 15 hospitals in Australia. Unlike the VISION trial, they did not previously receive docetaxel or 2nd line hormonal treatment for mCRPC. The risk factors were:

  1. metastatic at original diagnosis
  2. elevated LDH, ALP, albumin (PSA> 5 ng/ml)
  3. PSADT< 84 days
  4. < 3 years since diagnosis
  5. ≥5 bone or visceral metastases 
  6. pain requiring opiates
  7. received abiraterone for mHSPC (docetaxel for mHSPC was allowed)

After 20 months of follow-up, the outcomes were:

  • Median PSA Progression-Free Survival was 13.0 months for the combo vs 7.8 months for enza-only
  • Median Radiographic Progression-Free Survival was 16 months for the combo vs 12 months for enza-only
  • Percent with >50% PSA reduction was 93% for the combo vs 68% for enza-only
  • Percent with >90% PSA reduction was 78% for the combo vs 37% for enza-only
  • Too early for overall survival
  • Improvement in pain scores were 61% for the combo vs 27% for enza-only
  • Side effects for the combo vs enza-only were fatigue (75% vs 70%), nausea (47% vs 27%), and dry mouth (40% vs 10%).
  • 81% received all 4 doses of Pluvicto.

Based on these results, and pending later follow-up on overall survival, Pluvicto should be combined with enza.

Friday, October 28, 2022

Docetaxel Extends Enzalutamide Effectiveness

 Enzalutamide (Xtandi) is one of the two second-generation hormonal medications that has been proven to extend survival in men with metastatic castration-resistant prostate cancer (mCRPC). The other is abiraterone (Zytiga). A pilot study suggested that docetaxel can sometimes reverse enzalutamide resistance.

The PRESIDE randomized clinical trial (RCT) treated 687 mCRPC patients in 123 sites throughout Europe. All of them were given enzalutamide along with ADT. 271 started to fail (PSA increase or tumor increase on scans) after 13 weeks. Then they were randomized to receive either:

  1. Triplet therapy: Enzalutamide and docetaxel and ADT concurrently, or
  2. Docetaxel and ADT and placebo

The triplet therapy extended progression-free survival over docetaxel+ADT, indicating that enzalutamide remained effective. The increase was small, but statistically significant.

Treatment-related adverse events were similar in the two groups, which were mostly attributable to docetaxel.

The triplet group had more serious events - 49% vs 39%

This confirms the earlier Phase II CHEIRON RCT. CHEIRON proved that the combination could delay progression, but it did not improve overall survival.

In a similar RCT, called "ABIDO," a triplet with abiraterone and docetaxel was tried. In early results, toxicity, particularly neutropenia, was significantly worse for the triplet. There was no benefit to this triplet.

This is our first proof that resistance to enzalutamide can be reduced with docetaxel. It also shows that triplet therapy may be beneficial in patients who have already progressed to castration resistance. We would expect a larger effect if used at the first sign of castration resistance.

(Update 8/23) An RCT randomized 81 mCRPC patients to either abiraterone (abi) or abiraterone+cabazitaxel. The combination had superior results:

  • Radiographic progression-free survival was 14.8 months for the combination vs 6.4 months for abi alone.
  • Overall survival was 24.5 months for the combination vs 18.3 months for abi alone.
  • PSA declined more than 50% in 92%  of men using the combination vs 56% using abi alone.

Other combinations with abiraterone that have proved to be useful for patients with mCRPC include apalutamide+abiraterone (ACIS RCT), ipatisertib+abiraterone (IPATential150 RCT), and olaparib+abiraterone (PROpel RCT)-- Results for a PARP inhibitor+abiraterone were not as universally favorable in the MAGNITUDE RCT. Triplet therapy is already standard-of-care in newly diagnosed mHSPC (see this link).

Friday, June 3, 2022

Abiraterone/enzalutamide+PARP inhibitor better than abiraterone/enzalutamide alone for mCRPC


PARP inhibitors have been approved for men with metastatic castration-resistant prostate cancer (mCRPC) who have certain defects in their DNA-repair mechanism, mainly defects in their BRCA genes. So far, two PARP inhibitors have been approved: olaparib (Lynparza) after progression on abiraterone (Zytiga) or enzalutamide (Xtandi), and rucaparib (Rubraca) after a second-line hormonal medicine and docetaxel. Two other PARP inhibitors, niraparib (Zejula) and talazoparib (Talzenna) are not yet approved. (See this link). PARP inhibitors prevent cancer cells from fixing DNA mistakes that are more prevalent when one already has the defective BRCA gene.

Hypothetically, PARP inhibitors can delay progression in cancer cells whose DNA is already being disrupted by radiation: Xofigo or Pluvicto. Lynparza has been found to have no benefit when used with Keytruda. A trial of bipolar androgen therapy (BAT) with Lynparza found that the combination delayed progression considerably in men without DNA-damage repair defects. They may also be useful when cell replication is being slowed by docetaxel+carboplatin or second-line hormonals, even in men who do not have DNA damage repair defects. Enzalutamide may be able to prevent cross-resistance between docetaxel and PARP inhibitors (see this link)

The PROpel clinical trial randomized 796 mCRPC patients in 17 countries to get either:

  • abiraterone + olaparib, or
  • abiraterone + placebo
  • a quarter had already had docetaxel
  • none were previously treated with a second-line hormonal
  • all were tested (Foundation One) for DNA damage defects which were found in ~28% of patients

With about 21 months of follow-up, radiographic (any kind of imaging) progression-free survival (rPFS) was:

  • 25 months in the olaparib group vs 17 months without olaparib (HR=0.66)
  • Benefit did not differ significantly by type of metastasis, previous docetaxel, or whether they had pre-existing DNA damage repair defects

Follow-up was not long enough to detect significant differences in overall survival, but other secondary endpoints showed benefit for the combination:

  • PSA response was 79% with olaparib vs 69% without it
  • Time to PSA progression was not reached for olaparib vs 12 months without it
  • Tumors shrank in 58% with olaparib vs 48% without it
  • Time to next therapy was reduced by 26% due to olaparib
  • Time before progression on the next therapy was reduced by 31% due to the olaparib therapy
  • In an update, overall survival has increased to 42.1 mos. for the combination from 34.7 mos. with abi only - an improvement of 19%.
    • The improvement was greater in those with the DNA mutations (+34%) than in those without such mutations (+11%); the benefit was +71% in those who were BRCA+
    • Time to next therapy and time to next progression were also lengthened
    • QOL was not diminished by the combination vs the montherapy, although the usual adverse events associated with PARP inhibitors were observed (hematological side effects and fatigue mostly).
The FDA approved the combination, but only for patients with BRCA+ mutations.

Some adverse events were markedly increased among those taking olaparib:

  • any grade 3 was reported by 47% with olaparib vs 38% without it
  • interruption of the drug among 45% taking olaparib (33% interrupted abiraterone) vs 25% taking placebo (22% interrupted abiraterone)
  • dose reduction of the drug among 20% taking olaparib vs 6% taking placebo
  • discontinuation of the drug among 14% taking olaparib vs 8% taking placebo
  • anemia  among 46% (15% grade 3) taking olaparib vs 16% (3% grade 3) taking placebo
  • fatigue among 37% taking olaparib vs 28% taking placebo
  • nausea among 28% taking olaparib vs 13% taking placebo
  • diarrhea among 17% taking olaparib vs 9% taking placebo
  • decreased appetite among 15% taking olaparib vs 6% taking placebo
  • pulmonary embolism among 7% taking olaparib vs 2% taking placebo
(update 9/14/23) An update with overall survival (OS) was reported after 36.5 months of follow-up.
  • Mortality was 19% lower for olaparib than the placebo which was not statistically significant. 
  • Median OS was 42 months for olaparib vs 35 months for the placebo, but the difference was not quite statistically significant.
    • Those with HRR mutations were 34% less likely to die, which was statistically significant.
    • Those without HRR mutations were 11% less likely to die, which was not statistically significant.
  • There was no difference for the first 2 years of follow-up, but then the group taking olaparib did better.
  • The greatest benefit for the combination was in patients who had germline HRR mutations, and in patients who had BRCA+ mutations specifically.
  • Among those taking olaparib, 40% suffered a serious adverse events, particularly anemia (50% all-grade, 16% grade 3+).
  • Almost half of patients taking olaparib interrupted treatment due to an adverse event.

The TALAPRO-2 clinical trial randomized 1,037 mCRPC patients independent of their DNA-damage repair (DDR) defect status to one of 2 groups:
  • Talazoparib + enzalutamide +ADT ("tal-combo")
  • Placebo+enzalutamide+ADT ("enza")
In the first report:
  • radiographic progression-free survival (rPFS) increased by 37% for the tal-combo over enza alone
    • +54% among those with a DDR mutation
    • +30% among those without a DDR mutation
  • Improvements in any tumor response (61.7% vs 43.9%)
    • Improvements in complete tumor response (37.5% vs 18.2%)
  • 28% improvement in time to PSA progression
  • 51% improvement in time to chemotherapy
  • 22% improvement in time to QOL deterioration
  • Overall survival data is not yet mature (<50% have died in the enza group)
Side effects (mainly hematological) were significant:
  • ⅔ experienced anemia, for which 43% of tal-combo patients had to have a transfusion
  • Grade 3 or 4 (serious or life-threatening) adverse events occurred in 72% of the tal-combo group vs 41% of the enza group.
  • Other than hematological adverse effects, 34% experienced fatigue (vs 29% for enza), 22% experienced back pain (vs 18% for enza), 22% had decreased appetite (vs 16% for enza), and 21% had nausea (vs 12.5% for enza).
  • About 80% of patients were able to complete the tal-combo at full dose
Talapro-3 will determine if there is any benefit to earlier treatment - while men are still hormone-sensitive and have at least one DDR mutation.

The MAGNITUDE clinical trial randomized 423 mCRPC patients with (Arm 1)DNA repair defects and (Arm 2) 233 without DNA repair defects to: 

  • abiraterone + niraparib, or
  • abiraterone + placebo
  • 23% had prior abiraterone

After 19 months of follow-up, Arm 2, the group that did not have DNA repair defects was stopped for futility because there was no benefit in rPFS in that group.

Among those with DNA repair defects:

  • rPFS was 17 months with niraparib vs. 14 months with placebo
  • if they had BRCA defects, rPFS was 17 months with niraparib vs 11 months with placebo
  • time to chemotherapy was increased by 41% by niraparib
  • time to symptomatic progression was increased by 31% by niraparib
  • time to PSA progression was increased by 43% by niraparib
  • tumors more than doubled without niraparib vs with nirparib
  • discontinuation of the drug among 9% taking niraparib vs 3.8% taking placebo
  • Grade 3+ adverse events occurred in 67% taking niraparib vs 46% taking placebo
A more granular analysis of specific DNA repair genes suggests there may be a benefit (sample size is low) in men with defects in CHEK2.

In an update presented at ASCO, Eleni Efstathiou presented the following (note: benefits were always improved in the BRCA+ subgroup):
  • rPFS was 16.7 mos with nira+abi vs 13.7 mos. with placebo+abi
  • Time to symptomatic progression was lengthened by 40%
  • Time to chemotherapy was lengthened by 33%
  • Overall survival was unchanged, but the data is immature (too few people have died)
(Update 7/4/23) A second interim analysis at 24.8 months median follow-up showed:
  • rPFS was 19.5 mos with nira+abi vs 10.9 mos. with placebo+abi
  • Time to symptomatic progression was lengthened
  • Time to chemotherapy was lengthened 
  • Overall survival improved by 46% compared to those who did not initiate PARP inhibitors at any subsequent time. 
Eleni Efstathiou, the lead investigator of the MAGNITUDE trial, believes that the trial design explains why men without DNA repair defects benefited from the PARP inhibitor in the PROpel and TALAPRO-2 trials, but not in the MAGNITUDE trial. She believes that the subgroup that was stopped early might have shown some benefit if they had continued. I can also conjecture that:
  • Olaparib is a stronger PARP inhibitor (based on worse side effects)
  • The olaparib group was less progressed
  • The previous docetaxel use by ¼ in the olaparib trial sensitized the cancer, whereas the previous abiraterone use in the niraparib trial had no sensitization effect. 
(update 4/28/23) The FDA has decided to only approve the combination for patients who are BRCA+

(update 1/26/24) The BRCAAway trial randomized 61 BRCA+ and ATM+ mCRPC men to:
  1. abiraterone
  2. olaparib
  3. abiraterone+olaparib

In addition, men in Group 1 and 2 were allowed to cross over to the other medicine upon progression.

The results were:

  • Progression-free survival (PFS) was 8 months for abi, 14 months for olaparib, and 39 months for the combination.
  • Objective Response Rate (ORR) was 22% for abi, 14% for olaparib, and 33% for the combination
  • % of patients with PSA reduction of more than 50% (PSA50) was 61% for abi, 67% for olaparib, and 95% for the combination
  • Undetectable PSA was 17% for abi, 14% for olaparib, and 33% for the combination
  • Although patients responded to cross-over, it was never as good as starting with the combination
  • Adverse events were as expected for each medication

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)

(frequently updated)


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.
  • Selective Androgen Receptor Modulators (SARMs) may be able to provide similar benefits without some of the drawbacks (see this link).

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. Intermittent ADT is sometimes inferior to continuous androgen ablation, perhaps especially for those with low metastatic burden. Castration resistance occurs at the same time with either intermittent or continuous ADT, and intermittent has not been shown to prolong survival.

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 at least some 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. It does not increase survival (see the TRANSFORMER RCT below). However, 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.

How can we tell who will respond and who will get worse?

Markowski et al. reported on 6 men treated with BAT. A PSMA PET scan (DCFPyL) 3 months into BAT treatment revealed that 3 of them had already progressed to having new metastases.

Before it can gain widespread use, is imperative that predictive biomarkers be found. So far, genomic analysis has failed to discover any.

Can it overcome resistance to Zytiga or Xtandi?

(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 flare was the most common, affecting 40%. A few men suffered very serious side effects: pulmonary embolism, heart attack, urinary obstruction, gallstones and fatal sepsis.
(Update July 2020) In the RESTORE randomized clinical trial (RCT), 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.  They give monthly testosterone injections until there is radiographic progression. The RESTORE trial found that BAT was able to restore responsiveness to Xtandi but much less to Zytiga.
  • Following testosterone therapy, PSA declined by 50% in 30% of the group who'd previously taken Xtandi, and in 17% of the group who'd previously taken Zytiga. On these small groups, the difference wasn't statistically significant.
  • After BAT, PSA declined by ≥50% in 68% on rechallenge with Xtandi and lasted 13 months
  • After BAT, PSA declined by ≥50% in 16% on rechallenge with Zytiga and lasted 8 months
  • There was no benefit to rechallenge with either in men with the AR-V7 mutation
(Update December 2020) The "C-arm" of the RESTORE trial comprised 29 castration-resistant (mostly metastatic) patients who received only ADT but no second-line hormonal therapies. 
  • Only 4 men (14%) had a PSA decline ≥50% due to the testosterone therapy
  • Only 4 men had a reduction in their metastases. All of those had lymph node metastases only.
  • Testosterone therapy lasted for 9 months (median) before radiographic progression was detected
  • Maximum PSA response was achieved in 56 days. Only 7 patients had any PSA reduction.
  • PSA more than doubled in 52%, and increased markedly in 14% more.
  • 31% had some radiographic reduction of metastases.
  • Median radiographic progression-free survival was 8.5 months
  • Musculoskeletal pain was experienced by 40%
  • Other prevalent side effects were: hypertension (21%), breast tenderness (21%), leg swelling (17%), fatigue (14%), and difficulty breathing (10%). One patient died of a stroke.
  • 18 patients later received Zytiga or Xtandi, with excellent results.
  • There weren't any discernable genomic determinants of response.
Based on the RESTORE trial, this trial suggests that BAT should be reserved for patients who:
  1. have already progressed on Xtandi, or 
  2. a short duration of BAT may make the first use of Xtandi last longer. 
Both of those hypotheses should be tested in larger trials. It also brings into question whether PSA reduction should be used as an endpoint. PSMA PET/CT may be a better indicator of early progression on BAT (see this link). There is still no clue as to why only 31% respond.

In the TRANSFORMER RCT,  195 chemo-naive mCRPC men who failed therapy with Zytiga were randomized to receive either BAT or Xtandi. Everyone crossed over to the therapy they didn't previously get. With up to 2 years of follow-up:
  • Comparing BAT to Xtandi (before crossover), there were no significant differences in the time to clinical or radiographic progression (5.7 months in both groups) or reduction in PSA by ≥ 50% "PSA50" (28% and 25%)
  • After crossover, PSA50 was 78% for Zytiga->BAT->Xtandi vs 23% for Zytiga->Xtandi->BAT
  • After crossover, PSA-progression-free survival was 11 months for Zytiga->BAT->Xtandi vs 4 months for Zytiga->Xtandi->BAT
  • Those who went from Zytiga -> BAT -> Xtandi survived 37 months vs 29 months for those who went from Zytiga -> Xtandi (not significantly different)
  • BAT improved patient-evaluated quality of life
  • 3 patients received Keytruda after BAT and did very well. This observation led to the COMBAT trial using a different immune checkpoint inhibitor (Opdivo)
  • (update 5/7/24) Patients who never achieved serum T below 20 ng/dl did better with BAT than Xtandi.
Including BAT right after Zytiga failure and then using Xtandi increased the time to PSA progression, delayed radiographic progression, and reduced PSA. But waiting until after a failure on both drugs had no effect. This trial suggests that BAT may be useful after Zytiga but before Xtandi, particularly if T response to ADT has been less than optimal.

(Update Oct. 5, 2022) An exploratory analysis helps to explain why BAT has limited effectiveness (only 20-30% of  CRPC men derive any benefit from BAT), and what might be done to make it more effective. They focussed on the protein called c-MYC, which is known to be upregulated in advanced prostate cancer. They found:
  • High androgen receptor (AR) activity is required for BAT to work. Only about ⅓ of CRPC men have high AR activity.
  • But AR inhibition first is needed for T to raise its activity
  • High AR activity downregulates c-MYC. 
  • High doses of testosterone (T) increases AR activity.
  • Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits it.
AR activity (requiring tumor biopsy) may be a valuable biomarker.

They are running a clinical trial to test cycling between T and Xtandi after Zytiga failure.

(update January 2021) In the COMBAT trial, 45 heavily-pretreated men who were mCRPC and who have progressed on either Zytiga or Xtandi, received BAT followed by Opdivo (nivolumab - an immune checkpoint inhibitor).
  • ⅔ had at least some PSA reduction
  • 40% had a PSA reduction ≥ 50%
  • Median overall survival was 28 months
  • 24% had a measurable reduction in disease; 11% for 11 or more months
  • Median radiographic progression-free survival was 5.7 months
  • 1 patient had a complete PSA response
  • However, in 27% PSA got much worse after BAT
  • BAT seems to inhibit MYC - a genetic driver of prostate cancer
This trial suggests that BAT may prime prostate cancer cells so that they are more sensitive to checkpoint inhibitors.

(Updated 9/21/21) 30 heavily-pretreated men who were mCRPC and who have progressed on either Zytiga or Xtandi, received BAT and the PARP inhibitor olaparib. Half had DNA damage repair defects. This was hypothesized based on lab findings.
  • ¾ had at least some PSA reduction
  • 47% had a PSA reduction ≥ 50% (44% if 2 who dropped out for progression are added)
  • 23% had a 12-wk PSA increase ≥50% (28% if 2 who dropped out for progression are added)
  • Median progression-free survival was 14.8 months if they were mutation-free vs. 7.5 months if they had the defects.
  • 2 patients had a complete PSA response
  • 5 of 8 90+% responders were free of DNA damage repair defects
  • 3 of 6 90+% progressors had DNA damage repair defects
  • 5 patients had serious (grade ≥ 3) toxicity, including one death
This trial suggests that BAT + olaparib achieved good response regardless of DNA damage repair defect status. Excellent responders had mutations of the T53 gene or DNA repair genes (see this link). The cause of responder/non-responder differences remains elusive.

(update 6/3/2022) A small trial suggests that there may be genomic predictors. They found that some mCRPC patients got a better PSA response from BAT if they had germline (inherited) or somatic (tumor biopsy) genomic mutations of the tp53 gene and one of either RBI gene or PTEN gene loss. There are no clear indications - the results were mixed:
  • PSA decreased in 10 of 17 men with tp53 and PTEN loss
    • in 8, PSA decreased more than 50%
      • in 1, PSA became undetectable
  • PSA increased in 7 of 17 men with tp53 and PTEN loss
    • in 3 of those 7, PSA more than doubled
  • PSA decreased in 2 of 2 men with tp53 and RB1 loss
  • PSA increased in 3 of 3 men with RB1 and PTEN loss, so tp53 loss seems to be necessary for a BAT benefit
They also pointed out that in the recent trial of cabazitaxel+carboplatin at MD Anderson, the same genomic predictors of success were found. They propose a comparative trial of the 2 therapies in men who have mutations in tp53 and one of the two (either rb1 or pten).

(Update 11/8/2018) A new clinical trial at the University of Colorado, Denver will try transdermal testosterone instead of injections alternating with enzalutamide.

(update 6/2024) A new clinical trial at Roswell Park, Buffalo to restore sensitivity to ARSi.

(Update Jan 11, 2020) A new clinical trial at Johns Hopkins will combine BAT and Xofigo. Prior treatment with chemo and/or no more than one kind of second-line antiandrogen are allowed but not required. Recall that the RESTORE trial suggested that response was limited to lymph nodes only, so Xofigo may be a complementary treatment. Treatments that induce double strand breaks, like BAT and Xofigo, may be complementary, especially when combined with immunotherapy (see this link).

Other clinical trials include combining with Provenge, combining with Carboplatin, and using on patients who have genomic repair defects other than BRCA: ATM, CDK12, or CHEK2.

It will be important to determine, in future clinical trials, which men will respond to BAT and which men will not. Sadly, there may only be a survival benefit in a small subset of patients, although there is a quality of life benefit. Importantly, all clinical studies so far have only been Phase 2 trials in very small groups of patients. Larger trials will be necessary to prove safety and efficacy. There are already concerns about safety, so patients should not attempt BAT outside of a carefully monitored 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)? (see this link)
  • Does it have any benefit in men who have already had docetaxel chemotherapy? 
  • Considering that metastases shrank in some 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)?