Showing posts with label CHAARTED. Show all posts
Showing posts with label CHAARTED. Show all posts

Sunday, May 23, 2021

Abiraterone+docetaxel+ADT for newly diagnosed metastatic men beats docetaxel+ADT (or abiraterone+ADT)

The first results of the long-awaited PEACE-1 randomized clinical trial (RCT) are in. They randomized newly diagnosed metastatic men to either prostate radiation or abiraterone or standard-of-care (SOC). SOC included docetaxel for many of the men.

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). 

The full results will tell us how much the prostate radiation adds, and the effect on overall survival. The analysis by metastatic burden will be important too. Meanwhile, docetaxel+abiraterone+ADT should be considered the new standard of care.

How does this combination therapy compare to previous RCTs for docetaxel or abiraterone?

Because the STAMPEDE RCTs for docetaxel and abiraterone occurred at about the same time, 566 patients were randomized to one or the other. Sydes et al. reported the outcomes after a median of 4 years of follow-up. 
  • Abiraterone reduced PSA more quickly, as reflected in "failure-free survival" (time to PSA increase, clinical progression, or death) and "progression-free survival" (time to first "failure" event, excluding PSA). 
  • Those who received docetaxel first soon caught up. There were no significant differences in "metastasis-free survival," "prostate cancer-specific survival," "overall survival," or "time to the first skeletal-related event (pain or fracture)"
  • Serious toxicity (Grade 3 or greater) was also equal: 50% for docetaxel, 48% for abiraterone.

The STAMPEDE researchers (the STOPCAP group) did a meta-analysis of the STAMPEDE trials that concluded that abiraterone probably had a greater effect than docetaxel, but unlike the analysis above, it was not a direct comparison. They concluded that either should be recommended.

The other RCTs for metastatic hormone-sensitive prostate cancer (mHSPC) included STAMPEDE- abiraterone, LATITUDE- abiraterone, STAMPEDE-docetaxel, CHAARTED-docetaxel.GETUG-AFU-15(docetaxel) did not detect a difference in survival from the early use of docetaxel. 30% had prior treatment. There were differences in the populations studied in each trial that should be understood.

LATITUDE screened for more advanced patients - 80% were "high risk." High risk was defined by having 2 of 3 "high-risk" features, either: Gleason 8-10, or ≥ 3 bone metastases or visceral metastases. About half had performance status of 1 or 2 ("0" is the best performance status).

CHAARTED started by recruiting only patients with a high burden of metastases. But only 73% were de novo, meaning 27% had been previously treated before they entered the trial. They later opened the trial to men with fewer metastases and ended up with a small group (27%) of low burden de novo patients. They defined "high burden" as visceral metastases or ≥ 4 metastases with at least 1 outside the axial skeleton.

The two STAMPEDE trials recruited almost entirely (95%) de novo patients. 56% were "high burden" by the CHAARTED definition. 52% were "high risk" by the LATITUDE definition. 26% had performance status of 1 or 2.

PEACE1 recruited only de novo metastatic patients, with excellent performance status. 57% had high-risk features by the LATITUDE definition.

The following chart shows how long it took for patients to progress on each of the early interventions. Complicating analysis, each trial used a slightly different definition of progression.

Time to "progression" following each early therapy


abiraterone+docetaxel+ADT

docetaxel+ADT

abiraterone+ADT

ADT alone

Trial notes

PEACE1*

4.5 yrs

2.0 yrs



100% de novo, 100% perf. status 0, 57% high volume

STAMPEDE

(abiraterone)



Not reached (> 3.4 yrs)

2.0 yrs

94% de novo,26% perf.status 1 or 2, 55% high volume

LATITUDE*

(abiraterone)



2.8 yrs

1.2 yrs

100% de novo, 45% perf. Status 1 or 2, 80% high volume/high risk

STAMPEDE

(docetaxel)


3.1 yrs


1.7 yrs

95% de novo, 56% high volume

CHAARTED§

(docetaxel)


2.8 yrs


1.7 yrs

73% de novo, 65% high volume

* time to radiographic progression or death
time to first symptomatic event or death
§ time to symptoms or radiographic progression

While comparison is complicated, the extension of progression-free survival by 2.5 years by adding abiraterone to docetaxel alone is impressive. Docetaxel adds 1 - 1.5 years to progression-free survival over ADT alone. Abiraterone adds 1 - 1.5 years to progression-free survival over ADT alone.

Does docetaxel only benefit mHSPC patients with a high-volume of metastases?

This has stirred much controversy. Gravis et al. argue that the overall survival improvement from docetaxel was seen in CHAARTED only among men with high-volume metastases was a real biological effect (i.e., that high-volume PC is a different disease from low-volume PC, that responds differently to chemo). Armstrong argues for a biological difference. They acknowledge, however, that the small sample size of de novo men with low volume metastases (n=154) and their short follow-up (only 16% had died during the 48 months of follow-up) may be underestimating the benefit in the low volume, de novo subgroup. Remember that in CHAARTED, the low-volume subgroup was not recruited initially, so the follow-up is shorter in the group that needs the longer follow-up.

Clarke et al. argue that STAMPEDE is the more definitive trial because its sample size of mHSPC men with low-volume metastases was over twice as great (n=362) and the follow-up was longer (62% of the docetaxel patients had died during 78 months of follow-up). They did not find evidence of heterogeneity - low-volume PC responded just as much to chemo as high-volume PC. While the effect on low volume PC was similar, the statistical confidence in its effect did not meet 95% confidence. They attribute this to insufficient sample size (power). Suzman and Antonarakis agree that chemo should be offered to all mHSPC men, regardless of volume of metastases. It would seem that a meta-analysis combining the low-volume, de novo subgroups from both CHAARTED and STAMPEDE might be sufficiently powered to provide a more definitive answer. Patients wishing to understand why analyses of subgroups are controversial, may be amused by this analysis of STAMPEDE subgroups. The authors found that patients born on a Monday benefited the most from abiraterone, and it was statistically significant. while patients born on a Friday had the least benefit, and it wasn't statistically significant. They further found that men diagnosed on a Monday did not benefit from abiraterone, whereas men diagnosed on other days had a statistically significant benefit. These absurd findings are sometimes known as "p-hacking" or "data dredging." This interview discusses this error and the mistake of drawing biological inferences from statistical significance. Pre-specifying subgroups is one way to avoid such errors, but drawing conclusions from inadequately powered subgroups, while tempting, should be avoided. This controversy is reflected in the conflicting recommendations that constitute the standard of care.

The current NCCN guidelines state: "Docetaxel should not be offered to men with low volume metastatic prostate cancer, since this subgroup was not shown to have improved survival in either the ECOG study or a similar European (GETUG-AFU 15) trial." The current ASCO guidelines state: "Recommendation 1.2. For patients with low-volume metastatic disease (LVD) as defined per CHAARTED who are candidates for chemotherapy, docetaxel plus ADT should not be offered (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong for patients with LVD)." On the other hand, the current AUA/ASTRO/SUO guidelines state: "15. In patients with mHSPC, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel). (Strong Recommendation; Evidence Level: Grade A) Canadian Urological Assn (CUA) guidelines state: "Docetaxel plus ADT may also be an option in patients with mCNPC/mCSPC with good performance status with low-volume disease (Level 2, Weak recommendation)." NICE (UK) guidelines state: "Offer docetaxel chemotherapy to people with newly-diagnosed metastatic prostate cancer who do not have significant comorbidities." European Urological Assn (EAU) guidelines state: "Based on these data, upfront docetaxel combined with ADT should be considered as a standard in men presenting with metastases at first presentation provided they are fit enough to receive the drug [1070]"

I personally believe that the STAMPEDE researchers make a stronger case pending better data from PEACE1.

It is also possible that genomics will allow better selection of patients for early chemotherapy. Hamid et al. examined tissue collected for the CHAARTED trial. They found a subtype called "Luminal B" that was associated with improved survival from chemotherapy. This finding has not yet been validated on an independent trial. Meanwhile, DECIPHER provides the test as part of its GRID analysis.

The major advantages of early chemo vs "saving it for later" are:
  • Longer survival advantage
  • Side effects are milder when patients are less debilitated from years of cancer
  • As many as 10 infusions (usually 6) can be given if it is well tolerated
  • Most patients are not resistant, so docetaxel can be repeated
  • If there is resistance, cabazitaxel can be given


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: