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

Sunday, December 18, 2016

Small Cell Prostate Cancer Clinical Trials

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. 

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.

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. 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

There are two other DLL3-targeted immunotherapies in trials for SCLC that may turn out to be beneficial for NEPC as well. AMG757 is also a BiTE. 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)

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.

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 checkpoint blockade:
https://clinicaltrials.gov/ct2/show/NCT03582475
https://clinicaltrials.gov/ct2/show/NCT02643303
https://clinicaltrials.gov/ct2/show/NCT02475213
https://clinicaltrials.gov/ct2/show/NCT03179410
https://clinicaltrials.gov/ct2/show/NCT02791334
https://clinicaltrials.gov/ct2/show/NCT03229278


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