Showing posts with label immunotherapy. Show all posts
Showing posts with label immunotherapy. Show all posts

Sunday, February 3, 2019

Timing is everything with docetaxel (and hormone therapy and probably with immunotherapy and radiopharmaceuticals too)

The conventional wisdom with cancer is that "earlier is better." As cancers progress, they mutate: there are many more genetic errors in older cancers than in younger ones (see this link). Because of this, a therapy that may work well against a cancer in one stage of its development, may not work at all in an earlier or a later stage.

Prostate cancer is one of the most slow-growing of cancers in its early stages. This is why we can take so much time to decide on initial treatment, even in high-risk cases (see this link). It is also why low-risk men may safely choose active surveillance over immediate radical therapy. Progression is only weakly correlated with time since diagnosis, even for recurrences (see this link).

Early Use of Docetaxel

We have already seen that docetaxel is of limited (if any) use when combined with radiation therapy and ADT for high-risk cancer patients (see this link). It is also ineffective when combined with prostatectomy and ADT for high-risk cancer patients (see this link).

Oudard et al. conducted a randomized clinical trial of docetaxel+ADT vs ADT-alone in non-metastatic men with a recurrence after primary treatment. All 250 patients were "high risk," which was defined as at least one of the following:
  • Gleason score ≥ 8
  • PSA velocity > 0.75 ng/ml/year
  • PSADT ≤ 6 months
  • time to recurrence ≤ 12 months
Previous treatments were:
  • 73% had prior prostatectomy
  • 27% had prior primary radiotherapy ± ADT
  • 60% of men who had a prostatectomy also had salvage EBRT
The outcomes were as follows:
  • Median PSA progression-free survival was no different:19 months if they got docetaxel, 20 months if they didn't
  • Median time to radiographic progression was no different: 9 years in each group
  • There was no difference in 12-year overall survival rates: 60% in the docetaxel group, 55% in the no-docetaxel group. (The docetaxel group was 2 years younger)
  • Adverse hematological events from docetaxel included neutropenia (48%), febrile neutropenia (8%) and thrombocytopenia (3%)
CHAARTED showed that the survival increase attributable to docetaxel in recently-diagnosed, metastatic men was only observed among men with a high volume of metastases, but not among men with a low volume of metastases. "High volume" was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae. 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.

One small observational study suggested that docetaxel may benefit men who are castration-resistant but are not yet detectably metastatic. At the other end of the progression spectrum, in men who are both metastatic and castration-resistant, docetaxel added 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.

Docetaxel remains effective even after second-line hormonals (e.g., Zytiga, Xtandi) have stopped working. In fact, there have been cases where use of docetaxel has reversed resistance to them caused by the AR-V7 splice variant. However, combining docetaxel and Xtandi did not result in a survival advantage over docetaxel alone in a randomized clinical trial.

The "sweet spot" for docetaxel seems to be after there are detectable metastases but before castration resistance is fully established. Used earlier, it seems to have no effect in most men; used later, it is still effective, but less so.


Early Use of Hormone Therapy

It is well established that hormone therapy alone adds nothing to the survival of localized prostate cancer (see this link and this one). We also know that hormone therapy adds nothing to the effectiveness of radiation therapy for favorable risk prostate cancer (see this link and this one and this one). Even with recurrent prostate cancer post-prostatectomy, a major randomized clinical trial (RTOG 9601)  found that adding long-term antiandrogen therapy to radiation did not increase outcomes as much in men who had Gleason score ≤ 7, PSA ≤ 0.7 ng/ml or negative surgical margins.

However, an early analysis of the TOAD randomized clinical trial suggests that using androgen ablation on men who are recurrent after prostatectomy but not yet detectably metastatic may have a net survival benefit over the selective pressure it exerts towards castration resistance. In fact, men who started on ADT earlier developed castration resistance significantly later. This effect was also noted in the TROG 03.04 RADAR trial. The authors wrote, "The cumulative incidence of transition to castration resistance was significantly lower in men receiving [longer term ADT with their EBRT]."


Early Use of Second-line Hormone Therapy

We have learned that the use of abiraterone (Zytiga) in newly-diagnosed metastatic men increases survival markedly over waiting. 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 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 by16.8 months. Abiraterone was equally effective regardless of the number of metastases or whether they were classified as higher or lower risk (see this link).

Enzalutamide (Xtandi) is probably also beneficial if used earlier. A non-randomized clinical trial of early use of Xtandi showed it is very effective if used earlier (see this link), and a Phase 3 trial for its use in hormone-sensitive prostate cancer has had good results, according to a press release.

The FDA has approved apalutamide (Erleada) and enzalutamide (Xtandi) for use in non-metastatic castration-resistant prostate cancer. Darolutamide and abiraterone (Zytiga) will probably also be approved for this indication. Non-metastatic castration-resistant prostate cancer is probably an early version of metastatic castration-resistant prostate cancer, where micrometastases have not yet grown large enough to become detectable on a bone scan/CT.

Clinical trials suggest or are in process to determine if there is a role for advanced hormonal agents even earlier; for example in any of the following early settings:

• as part of an active surveillance protocol for men with favorable risk prostate cancer (see this link)
• adjuvant to radiation in high-risk localized prostate cancer (see this link)
• when it as advanced to only as far as pelvic lymph nodes (Stage N1 M0) (see this link)
• when it is recurrent but not yet detectably metastatic (see this link)

Early Use of Immunotherapy

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 in one small study (see this link). There are several clinical trials to help determine whether immunotherapy can play a role in extending the time that a man can stay on active surveillance (see this link and this one and this one).

In the "CHECKMATE 650" clinical trial of a combination of the two checkpoint inhibitor-type immunotherapies, nivolumab (Opdivo) and ipilimumab (Yervoy), there was some response (in 25% of pre-chemo men and 10% of post chemo men) from the combination, but no response from either drug alone in earlier trials. However, all of the responders  (60% of the pre-chemo group and 40% of the post-chemo group) had a high mutational burden and/or showed the presence of PD-L1 in the tumors (33% of the pre-chemo group and 19% of the post chemo group). Conversely, none of the men who had low mutational burden or PD-L1 had any response to the combination therapy. Toxicity was unacceptably high. This indicates that the cancer must evolve to a high degree of genetic breakdown before such therapies become effective. Early use causes unacceptable toxicity without any survival benefit.

At some point, cancer cells start displaying antigens that can be recognized by the immune system as "non-self," but it is not clear when that occurs in prostate cancer progression. Perhaps the fragments generated by chemo or radiation may make the cancer more susceptible to immune attack (see this link). It is also unclear when immune infiltration into tumors can occur, when checkpoint inhibitors (like PD-L1) begin to appear, and when regulatory T cells are overwhelmed by killer T-cells. Pro- and anti-inflammatory cytokines undoubtedly play a role in immune signaling and may occur at different stages.

Early Use of Radiopharmaceuticals

The ideal candidate for Xofigo will get all 6 treatments, preferably earlier, while bone health is still good (see this link). It has been found to work better on smaller tumors, so it is best used earlier rather than later (see this link). Because the combination of Xofigo and Zytiga caused excessive fractures and deaths (see this link), they can't be given simultaneously, at least not without a bone-preserving agent (like Zometa or Xgeva). Since a full cycle is completed in 24 weeks, taking Xofigo before Zytiga allows one to get the benefit of both in less time.

We do not know enough about the natural history of PSMA yet. We don't know when the PSMA protein first appears on the tumor surface. It has been detected in "high risk" patients, and is more often associated with higher grade cancer and in men with higher PSAs (see this link and this one). It as been detected in up to 95% of metastases. PSMA-based PET scans (Ga-68-PSMA-11 or DCFPyL) are used to check for PSMA-avidity before treatment. Without significant PSMA, the radiopharmaceutical would have nothing to latch onto, and might cause toxicity with no cancer-killing benefit.

A pilot test in South Africa suggests that Ac-225-PSMA-617 had good efficacy in patients who were not heavily pretreated, but their cancer was more progressed when treated. A trial with Lu-177-PSMA found that overall survival was 11 months in patients who had already had chemo (and were more progressed) and was 27 months in chemo-naive patients (who were also less progressed). Earlier seems to be better.


Although it is generally true that earlier treatment is better, we have learned that there are exceptions. There is tremendous individual variation, and it is likely that the window of opportunity varies.

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


Saturday, August 27, 2016

How do cancer cells that only absorb a sublethal dose of radiation get destroyed by the immune system?


In a recent article on combined radiation and immune therapy, I made the following statement without further explanation: “Radiation-modified cancer cells that escaped direct annihilation become more immune-susceptible too.” This effect is known as “immune modulation” and has previously been observed in test tube and mouse studies in castrate-resistant prostate cancer cells. A new study by Gameiro et al. of NCI/NIH extends the observation to the kind of cells responsible for hormone-sensitive bone metastases, and provides a biochemical mechanism for the observed effect. Because radiation alone only results in weak immune modulation, it is hoped that by understanding the precise mechanism responsible for radiation-induced killing of cancer cells by cytotoxic T cells, called “immunogenic cell death”, we can tailor therapies given along with radiation to enhance and sustain the immune modulation effect.

The precise mechanism is very complex. The radiation causes stress on internal components of the cancer cell. In an effort to recover, the cell activates its antigen-presenting machinery, and a protein called calreticulin moves to the cell surface where it attracts cytotoxic T cells.

This study provides a rationale for the use of immunotherapy to enhance the cancer cell killing of radiation alone. It also identifies stages in the process that can potentially be inhibited or enhanced by biochemicals and other molecules. Clinical trials will determine which immune enhancements are most effective.


This study was conducted by the National Cancer Institute of NIH. It is the kind of painstaking basic medical research that is critical to the development of new and improved therapies, and the kind that private companies and even universities are often reluctant to undertake because the rewards, if any, are so far in the future.

As a side note, it's worth mentioning that adjuvant ADT and radiation seem to work synergistically to enhance the immune effect. One can read about evidence of the combined effect of ADT and immunotherapy in a recent review by Antonarakis and Drake. One of the open questions is the optimal timing of all three therapies. In one mouse study, the authors conclude: “These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.” However, another mouse study draws the opposite conclusion: “androgen ablation improved immune responses to vaccination only when applied after immunization.” They are only mouse studies, so it’s difficult to draw conclusions about humans, but they illustrate that there is much still to be learned about all this.

The synergy of combining radiation and immunotherapy in the treatment of prostate cancer

Finkelstein et al have written an excellent review of the current understanding of this emerging and complex field. In contrast to some earlier studies that showed that radiation depressed the gamut of white blood cell types (e.g., Johnke et al, 2005), recent studies have shown that any such radiation-induced leukocyte suppression in high risk men is temporary, and there is a long-lasting enhancement of the anti-cancer immune response. The discrepancy with earlier findings may be due to higher doses of radiation used now, or the higher-precision radiation fields. There is also some evidence that the effect may vary with the kind of prostate cancer, the phenotype, associated with different risk levels, pelvic lymph node radiation, and by the way the dose is given (e.g. LDR brachytherapy vs SBRT). 

In fact, the authors find the opposite of the conventional wisdom to be true: radiation has an immune stimulatory effect when used on men with high-risk prostate cancer. There is an opportunity to bolster this effect when treating high-risk men with radiotherapy -- initial prostate radiation, salvage radiation after surgery, or radiation to isolated metastases. If this effect is maximized, there is a hope of killing off systemic micrometastases and tumors well outside of the radiation field. This is called the abscopal or bystander effect.

Radiation kills cancer cells, and the cellular debris is a source of antigens. Dendritic cells learn to use those antigens to activate killer T cells that then seek out and destroy cancer cells elsewhere that express those antigens. The damaged cancer cells also signal a host of other tumor-toxic molecules to form. Radiation-modified cancer cells that escaped direct annihilation become more immune-susceptible too.

Provenge, a dendritic cell boost coupled with immune-stimulatory factors, seems to be a perfect companion to radiation. There is a randomized clinical trial (NCT01807065) at the City of Hope to determine whether Provenge's effectiveness is enhanced by radiation to a single metastasis in men with mCRPC. [Update 2019: Twardowski et al. reported that progression-free survival was 3.7 months among those who received Provenge after SBRT vs. 2.5 months if they received Provenge without SBRT. This did not reach statistical significance (p=0.06) on this small sample (about 25 in each arm).]

(Update 2/2020) A small trial randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. Xofigo (radium 223 chloride) is a radioactive drug that destroys bone metastases. After median follow-up of 5.3 months:
  • Median progression-free survival was 10.7 months for the combination vs 3.1 months for Provenge alone.
  • The % who had a PSA reduction by more than half was 33% for the combination vs 0% for Provenge alone
  • The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
  • There were no increases in side effects for the combination

But immune stimulation will never be longlasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one's own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These "checkpoint blockers" are currently represented by drugs that have been FDA-approved for use in other cancers: Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor). "Ipi"+ radiation for mCRPC has been tried in two pilot tests. In one, patients were given radiation to a single bone met followed by ipi or a placebo, but the addition of ipi did not significantly increase survival.  In another study, patients were randomly assigned to get ipi+radiation or ipi alone. Both the PSA and the bone met response was good, and about the same for both groups. A larger study in 799 patients of ipi + radiation vs radiation alone confirmed the lack of effect (except in select subgroups) with 10 months of follow-up , but...

(update 8/2020) There was better news after the 799 patients were followed for a longer time. In an update by Fizazi et al 2.4 years later, ipi did increase survival in mCRPC patients, all of whom already had docetaxel, who received a single dose (8 Gy) of radiotherapy (SBRT) to one or up to 5 bone metastases. The effect reversed over time.
  • From 0-5 months post-SBRT, survival was 49% worse among those who got ipi
  • After 5 months post-SBRT, survival was ⅓ better among those who got ipi
  • At 2 years, survival was 25% with ipi vs 17% without ipi
  • At 5 years, survival was 8% with ipi vs 3% without ipi
  • Ipi drug toxicity caused death in 7 patients
  • The effect was the same for those with ≤5 or >5 bone metastases
It may be that those who died in the first few months were already beyond being helped, and the ipi toxicity harmed rather than helped them. Ipi alone has been found to have no effect on survival of mCRPC patients, even when used before docetaxel (see this link). SBRT to bone metastases has not been shown to increase survival (this is the subject of ongoing clinical trials). It is encouraging that the combination has some effect.

A new immunotherapy, ProstAtak, is being tested with radiation for localized PC (NCT01436968).

Some have suggested that several hypofractionated doses of radiation maximize the immune effect. To that end, UVA initiated a clinical trial (NCT02284971) of an experimental immune stimulant,Varlilumab, coupled with SBRT in 5 doses to the prostate and/or metastases in men with CRPC; however, the trial was terminated due to low accrual.

Other immune stimulants, like Leukine, have been used effectively in mice, and by some clinicians in human patients. It is likely that the optimal immune combo with radiation will include a front-end stimulant and a back-end checkpoint blocker.

Adding androgen blockade may enhance the immune effect still further (Antonarakis & Drake), and radiosensitize the tumors.

There are many unanswered questions:

  • Will the abscopal effect be any better in men who are metastatic but still hormone sensitive? 
  • Is the abscopal effect maximized with both dendritic cell enhancement and checkpoint blockade, or is the combination too toxic? 
  • Does Keytruda work better than Yervoy? 
  • What is the optimal timing of radiotherapy and immunotherapy? Should Provenge be used before, during, or after radiotherapy? 
  • For how long is the abscopal effect sustained? 
  • Is there still an abscopal effect when lymph nodes are irradiated? 
  • Does the abscopal effect increase with the number of metastases irradiated? 
  • Is there an abscopal effect with Lu-177-PSMA (this is the subject of a clinical trial at UCSF)?
  • Will a PARP inhibitor further enhance the abscopal effect? 
  • Can the abscopal effect be utilized for rare types of prostate cancer (e.g., neuroendocrine or undifferentiated)? 
  • Are there any genomics or biomarkers that are predictive or prognostic? 

written December 25, 2014 and updated since