Showing posts with label chemo. Show all posts
Showing posts with label chemo. Show all posts

Sunday, May 23, 2021

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

(Updated)

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.

(Update 9/19/21) Karim Fizazi presented the following chart at the ESMO Congress today:


Combining docetaxel and abiraterone in men who were originally diagnosed with high volume metastases increased overall survival significantly over either 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


Sunday, December 18, 2016

Small Cell Prostate Cancer Clinical Trials

(frequently updated)

Small Cell Prostate Cancer (SCPC), and more generally Neuroendocrine Prostate Cancer (NEPC), are thankfully rare types of prostate cancers. They are not responsive to hormone therapy, to taxanes (Taxotere or Jevtana), or to radiation. They are difficult to detect and monitor with the kinds of imaging used to detect prostate adenocarcinoma (mpMRI, bone scans, PSMA PET scans), but may show up with FDG PET (see this link). They do not put out PSA, PAP or bone alkaline phosphatase. Special biochemical tests or biopsies for chromogranin A, neuron-specific enolase (NSE), synaptophysin,  DLL-3, CD56, and other biomarkers are required. It often appears at a "mixed type." 

Sub-types

Not all neuroendocrine prostate cancers carry the same prognosis. Aggarwal identified a sub-type that became prevalent in 17% of patients who were heavily pretreated with enzalutamide (Xtandi) and abiraterone (Zytiga). He calls this "treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC). The pre-treatment probably selected for this subtype that may be partially responsive to familiar therapies. The "treatment-emergent" subtype and the small amounts sometimes detected initial biopsies do not appear to be as virulent (see this link). There are some studies that indicate that they may appear spontaneously in later stages of normal prostate cancer development. Aggarwal commented:
“Although long term androgen deprivation therapy may be associated with the development of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in a minority of patients, multiple studies have confirmed the long-term benefit of abiraterone and enzalutamide for prostate cancer patients in various disease settings. Use of these agents should not be limited by concern for the subsequent development of t-SCNC.”
Aggarwal has announced a clinical trial where he will be testing a combination of Xtandi, Keytruda, and ZEN-3694 in (among others) a group of men identified with the t-SCNC subtype. ZEN-3694 is an experimental medicine that inhibits a gene called MYC, which is often over-expressed in advanced prostate cancer. 

Aggarwal is also testing FOR-46 targeting the CD-46 protein that often is expressed in neuroendocrine tumors.

Chemotherapy

Because of the "mixed type," chemo often includes a taxane. More often, a platin is mixed in a cocktail with another chemo agent, like etoposide. A couple of case reports from Japan (see this link and this one) reported some success with a platin combined with irinotecan.

This clinical trial at Duke has two chemotherapies (cabazitaxel and carboplatin), as well as two checkpoint blockade-type immunotherapies (nivolumab and ipilimumab):
https://clinicaltrials.gov/ct2/show/NCT04709276

Nuclear Medicine/ Somatostatin

Perhaps the most promising treatment to date has been tried by the nuclear medicine department at the University of Heidelberg. I suggest that anyone who is interested email or call (they all speak English) Uwe_Haberkorn@med.uni-heidelberg.de Phone: 06221/56 7731. With the euro now at close to parity with the dollar, this medical tourism is an especially attractive option:

213Bi-DOTATOC shows efficacy in targeting neuroendocrine tumors

A similar radiopharmaceutical using Lu-177-DOTATATE (called Lutathera) has been FDA-approved for small cell cancer affecting the digestive tract. DOTATOC (and also DOTATEC and DOTATATE) binds to somatostatin receptors on the small cell digestive tract cancer surface, where it is highly expressed. It is rarely expressed in small cell prostate cancer, but there have been some isolated case reports like this one or small trials like this one. This means that treatment with a somatostatin analog (octreotide, lanreotide, or pasireotide) may be somewhat effective even without the radioactive emitter attached to it. These drugs are available now in the US, are not toxic, and your doctor can prescribe them without a clinical trial. there is a clinical trial of it in London for any solid tumor:

https://clinicaltrials.gov/ct2/show/NCT02236910

These clinical trials include somatostatins:

https://clinicaltrials.gov/ct2/show/NCT01794793
https://clinicaltrials.gov/ct2/show/NCT02754297

While the presence of somatostatin receptors in the tumor can be determined by pathological analysis (immunohistochemical (IHC) staining for SSTR2), there is an FDA-approved PET scan that uses Ga-68-DOTATATE that can detect it without a biopsy. It is used to detect neuroendocrine tumors that are often non-prostatic. Researchers at Emory found that Ga-68-DOTATATE uptake is higher even in neuroendocrine tumors of prostatic origin, which suggests that somatostatin-based therapy may be beneficial. (One patient who was positive for a BRCA2 mutation but negative for NEPC had high uptake as well.)

DLL3

DLL3 is a protein that is expressed on the surface of neuroendocrine cells regardless of the cancer of origin, and has been identified in two-thirds of neuroendocrine prostate cancer (NEPC) cells. An antibody linked to a chemotherapy, called Rova-T, against DLL3 has been developed and has shown some promise against NEPC in a preclinical study. Unfortunately, AbbVie discontinued R&D after it failed to meet goals for small cell lung cancer (SCLC). A Phase 2 trial that included NEPC was discontinued. Misha Beltran at Dana Farber has tried an antibody-drug conjugate (rovalpituzumab teserine) targeted to DLL3 on a single patient. After two treatments, his metastases shrank and stabilized.

Harpoon has announced a clinical trial of HPN328  for people with advanced cancers that express DLL3. HPN328 is a bispecific T-cell engager (BiTE) that targets DLL3 and also promotes T cells to attack those cells exhibiting it. AMG757 is also a BiTE. Amgen has announced a clinical trial of AMG 757 for advanced prostate cancer. 

AMG119 is a CAR-T therapy that targets DLL-3. CAR-T involves treating one's own T-cells by sensitizing them to DLL3. Both of these create a T-cell and a cytokine response in environments that otherwise have low immune cell activity. That response may kill bystander cells, and through a phenomenon called "antigen spreading," may be able to kill other cancer cells that do not exhibit DLL3. (BiTE and CAR-T therapies that target PSMA are  in clinical trials noted at end of this article)

The Wang Lab at Duke has specific expertise in morphological analysis of NEPC and IHC staining for DLL3. It may be a good idea to get a second opinion from them.

Checkpoint blockade

Another recent discovery that gives a lot of hope is that PD-L1 is highly expressed in SCPC. This opens the door to immunotherapies that target the PD-1/PD-L1 pathway, like Keytruda.

PD-L1 expression in small cell neuroendocrine carcinomas

Several clinical trials use PD-L1 checkpoint blockade:

Sunday, August 28, 2016

Chemo+ADT+RT: No benefit after ten years


Earlier this month, we looked at the evidence of benefit for adding chemo to radiation therapy for high-risk prostate cancer (see “Docetaxel with radiation in prostate cancer treatment”). Early results of RTOG 0521 showed only a modest benefit in the short term. Would longer term follow up reveal a greater benefit?

We now have a ten-year update of RTOG 9902, a clinical trial begun in 2000 and closed to accrual in 2004 because of excess toxicity. Although the study ended before it met its accrual goal, patients continued to be tracked. The study protocol included:
  • ·      380 high-risk patients were randomized to two arms
  • ·      High Risk:
o   Gleason score≥7 and PSA from 20 to 100 ng/ml or
o   Gleason score≥8 and stage≥T2
  • ·      Two arms:
o   Chemo + ADT + RT
o   ADT + RT
  • ·      Chemo: Paclitaxel + Estramustine + Etoposide
  • ·      ADT: LHRH agonist (24 months) + anti-androgen (4 months), both begun 2 months before RT
  • ·      RT: 70 Gy
The ten-year results were as follows:
  • ·      Overall survival: 63% with chemo, 65% without chemo (no sig. difference)
  • ·      Local progression: 7% with chemo, 11% without chemo (no sig. difference)
  • ·      Distant metastases: 14% with chemo, 16% without chemo (no sig. difference)
  • ·      Disease-free survival: 26% with chemo, 22% without chemo (no sig. difference)
Before we write off adjuvant chemo with radiation entirely, we must acknowledge that the clinical trial was begun before docetaxel became available. Docetaxel is far more effective and far less toxic than the chemo used in this study. They also used a radiation dose of only 70 Gy, which we now know to be inadequate for high-risk patients. So far, all we can conclude is that we don’t have enough evidence to change the standard of care to include chemo with radiation.





Docetaxel with primary radiation therapy for high risk prostate cancer


In 2004, the FDA approved docetaxel as the first chemotherapy drug proven to extend survival in metastatic hormone-refractory prostate cancer. Although the survival benefit was a modest 2.5 months, researchers launched clinical trials to determine whether the survival advantage could be increased by using docetaxel earlier in disease progression or by combining it with other therapies. Those trials are beginning to mature now.

Last year, the CHAARTED study demonstrated a 17-month survival advantage stemming from starting docetaxel at the same time as ADT in men with multiple metastases. However, another trial, GETUG-AFU 15, did not demonstrate a benefit. Last month, early reports of the STAMPEDE trial confirmed the benefit, which was 22 months among men with any metastases upon initial diagnosis. As in the CHAARTED trial, the evidence of benefit has not yet emerged among men with advanced cancer who did not yet evince metastases.

Several trials looked at combining docetaxel with radiation among men diagnosed with high risk localized prostate cancer. RTOG 0521 showed that the 4-year overall survival was 89% without docetaxel and 93% with it -- a statistically significant difference, but perhaps not as meaningful as we would have liked to see. There was a significant improvement in disease-free survival (65% vs. 55% at 6 years), and incidence of metastases at 6 years (9% vs 14%). It’s possible that with longer follow up, the difference in overall survival will increase in magnitude.

Another clinical trial, GETUG-12, was designed to find out whether chemotherapy (docetaxel + estramustine) pretreatment would provide a survival benefit when added to 3 years of ADT and RT begun 3 months from the start of chemo (in 87% of the patients). The study was described and early results given in 2010, so I will not go into the details again. However, some follow-up results have recently been published. (Update 12/4/2018Fizazi et al. report that after 9.6 years median follow-up, relapse-free survival was 11.6 years among those who received chemo versus 8.1 years among those who did not. Clinical/radiographic relapse-free survival was 13.9 years among those who received chemo versus 12.5 years among those who did not. Metastasis-free survival, prostate cancer- specific survival, and overall survival were not significantly different. They further report equal levels of late-term high-grade side effects in both groups, and no deaths attributable to the chemotherapy.

These are not yet the improvements in long-term survival that we eventually hope to see by adding docetaxel. The long wait for differences in survival once again highlights the very long natural history of the disease, even in men diagnosed with high-risk prostate cancer.


(Update: 6/28/2018) A Scandinavian trial (SPCG-13) reported no benefit to adding docetaxel after ADT+RT in unfavorable risk patients. 376 patients with unfavorable intermediate risk or high risk prostate cancer were randomized to receive either:

A. RT (at least 74 Gy) +ADT followed by docetaxel (75mg/m2) every 3 weeks for 6 cycles
B. RT (at least 74 Gy) +ADT

After 5 years of follow-up:
  • The rate of biochemical failure was the same for both groups, at about 30%.
  • There were 20 deaths in Group A, 9 attributable to prostate cancer
  • There were 23 deaths in Group B, 7 attributable to prostate cancer
  • Febrile neutropenia, which can be life-threatening, occurred in 17% of Group A.
Five years should be long enough to start seeing a difference in biochemical failure rates, but none was observed and the survival curves showed no signs of diverging. Based on this clinical trial, there was no benefit, but substantial risk to adding docetaxel after RT+ADT in unfavorable risk patients.

(Update 10/16/2018) A small (n=132) Spanish trial  (more details here) also found no benefit to adding docetaxel to RT+ADT in high risk men. Patients were randomized to one of two groups:

A. RT (74 Gy) +ADT (LHRH agonist for 3 years)
B. RT+ADT (as above) followed by 9 weekly cycles of docetaxel (20 mg/m2)

Patient characteristics were:
  • Stage T3/4: 81%
  • Gleason score ≥ 8: 77%
  • PSA>20: 29%
  • positive lymph nodes: 18%
After 5 years of follow-up:
  • Biochemical recurrence-free survival was not statistically different: 93% for Group A, 85% for Group B
  • Progression-free survival was not statistically different: 93% for Group A, 84% for Group B
  • Overall survival was not statistically different: 93% for Group A, 94% for Group B