Showing posts with label clinical trial. Show all posts
Showing posts with label clinical trial. Show all posts

Tuesday, August 11, 2020

PSMA-targeted radiopharmaceutical clinical trials in the US

Now that the VISION trial of Lu-177-PSMA-617 is no longer recruiting, some patients are wondering if they can still get PSMA-targeted radiopharmaceuticals in the US, without traveling to Germany, Australia, India, etc. Here is a list of trials that are active, still open to recruitment, or will soon be recruiting. 

Unless otherwise noted, they are all for men who are: 

  • metastatic
  • castration-resistant 
  • have had at least one taxane chemotherapy
  • at least one of the advanced androgen receptor therapies (e.g., Zytiga, Xtandi, Erleada, or Nubeqa)
  • no Xofigo
  • PSMA-avid on a PSMA PET/CT scan

Radiopharmaceutical

Adjuvant drugs

Extra criteria

Recruitment status/ contact

Locations

Lu-177-PSMA-617

 

Chemo and immunotherapy naïve, failed one hormonal

Recruiting

(Phase 3 RCT)

• Omaha, NE

• Spain

• France

Lu-177-PSMA-617


mHSPC

(M1 or N1)

Treatment naive

Recruiting

• Omaha, NE

• Spain

• France

Lu-177-PSMA-617

Keytruda

No chemo since castration resistant

recruiting

UCSF

Lu-177-CTT1403

 

No Jevtana

recruiting

UCSF

Lu-177-PSMA-617

 

 

recruiting

•Weill Cornell

•Tulane (not yet)

Th-227-Antibody

(see article)

 

 

recruiting

• Royal Marsden (UK)

• Finland

• Tulane

• MSK

• Omaha, NE

Lu-177-J591

Ketoconazole

Prior RP or RT

CRPC

Non-metastatic

recruiting

• Weill Cornell

• USC

• Georgetown

• IU

• U of Iowa

• UPMC

Lu-177-PSMA-R2

 

 

recruiting

• Stanford

• Yale

• Tulane

• Johns Hopkins

• Mt Sinai

• MD Anderson

• U of Wisconsin

• Phoenix

Ac-225-J591

 

 

recruiting

• Weill Cornell

• Brooklyn Methodist

Ac-225-J591 + Lu-177-PSMA- I&T

 

 

Begins June 2021

• Weill Cornell

• Brooklyn Methodist

Ac-225-J91

Keytruda

No chemo since castration resistant

Begins June 2021

• Weill Cornell

• Brooklyn Methodist

• Dana Farber

• Columbia

Cu-67-SAR-bisPSMA

 

Previous chemo OK, not required

Begins Sept 2021

• Johns Hopkins

•Mayo Rochester

•Mayo, AZ

•Tulane, N.O.

•Barnes Jewish, St. Louis

•Omaha, NE

•Weill Cornell

Lu-177-PSMA-617

(VISION)

 

 

Active, not recruiting

• 84 locations

Results expected August 2020

I-131-1095-MIPS

(see article)

Xtandi

Chemo naïve

Failed Zytiga

Active, not recruiting

• 17 locations

Results expected December 2021


Tuesday, October 30, 2018

Newest radiopharmaceutical: Th-227-PSMA-antibody

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

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

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

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

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

Thursday, October 11, 2018

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

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

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

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

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

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

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

Wednesday, January 24, 2018

Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:
  • All patients will receive 34 Gy in 5 fractions to the prostate bed. 
  • There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
  • Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
  • Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 
While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.
  • Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
  • Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
  • For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
  • For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.
SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:
  • The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
  • The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
  • The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
  • Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.
We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

Tuesday, June 6, 2017

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.61

An unplanned secondary analysis presented at ESMO 2018 and published in European Urology looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

Early use of Zytiga+Docetaxel

Overall survival is not available yet, but radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). See discussion of early results of PEACE1.

Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The no-brainer here is Zometa+Celebrex. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43 month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel. However, the use of Zometa when one is still hormone-sensitive is controversial. An argument can be made for putting it off until there is evidence of osteoporosis on a DEXA scan - the risk of the worst side effect- osteonecrosis of the jaw - increases with the amount of time taking it.

The hormonal therapies have differing modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting. 

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

The PEACE-1 trial showed that the combination of docetaxel and Zytiga improved outcomes significantly.

A major clinical trial, ACIS, found that the combination of Erleada and Zytiga increased radiographic progression-free survival in men who were already castration-resistant. That combination improved results (in the AASUR trial) when given as an adjuvant therapy along with prostate radiation to men with very high-risk localized prostate cancer, and will be testedamong high-risk patients with high Decipher scores in the PREDICT-RT trial. The combination is being tried along with salvage radiation in men who have failed prostatectomy in the INNOVATE trial. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival has not been reached with the limited follow-up of the STAMPEDE trial, but we can look at 60% survival and  note that the curves are diverging, so the median survival improvement is at least this large. In STAMPEDE, early Zytiga increased median survival by at least 18 months; In LATITUDE, early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These are no longer recruiting:
These are still recruiting: