Ipilimumab (Yervoy) fails to increase survival, even when used earlier

Ipilimumab (Yervoy) is a type of immunotherapy that is known as a "checkpoint blocker." It blocks a protein in T-cells (called CTLA-4) that tells the immune system to stand down and not attack the cancer cells. It turns off the off-switch. The hope is that immune response against the cancer will continue longer than it ordinarily would.

A previous trial showed that Yervoy did not extend survival when used in men who were metastatic and castration-resistant  (mCRPC) and who had failed chemotherapy. This is often the first group given a new drug because other options have been exhausted and because it takes less time to prove efficacy. Researchers hoped that it might have some effect if used earlier in disease progression. Unfortunately, it did not.

Beer et al. tested Yervoy this time in men who were metastatic and castration-resistant but who had not yet tried chemotherapy and who were asymptomatic or minimally symptomatic (i.e., no bone pain or organ dysfunction). In this multi-institutional study, there were 399 patients who got Yervoy, and 199 who got a placebo. Neither patients nor doctors knew who got which.

• Patients were given 10 mg/kg of Yervoy or placebo every 3 weeks for up to 4 doses.
• Therapy was repeated every 3 months thereafter to non-progressing patients

The outcomes were as follows:

• Median overall survival was 28.7 months for those who got Yervoy vs. 29.7 months for those who got the placebo (no statistically significant difference).
• Median progression-free survival was 5.6 months or those who got Yervoy vs. 3.8 months for those who got the placebo (a statistically significant difference).
• 23% had a PSA response with Yervoy vs. 8% with the placebo.

The treatment-related adverse responses were:

• Death that was treatment-related in 9 patients (2%).
• Serious or life-threatening immune-related adverse events in 31%
• Serious or life-threatening diarrhea in 15%

While there was a PSA  response, and an increased time during which more patients taking Yervoy were progression free, this did not translate to a lengthening of overall survival. This may be because there was a subset of patients who had a good initial response, but the response was not sustained. This also shows the difficulty of measuring the response to immunotherapy using PSA or other surrogate endpoint. We know that Provenge, the only approved immunotherapy for prostate cancer, lengthens survival without reducing PSA. Here, the converse is true.

Research continues on other checkpoint blockers. Keytruda has been approved for melanoma, lung cancer and head-and-neck cancer. In addition to Keytruda, there are several investigational immunotherapies targeting the PD-1/PD-L1 antigen. It may turn out that checkpoint blockers work better in combination with other immunotherapies (like Provenge or ProstVac), or perhaps they need to be primed with concurrent SBRT radiotherapy or chemotherapy. We need a better understanding about why an immunotherapy may work very well for one cancer, but very poorly for another cancer, We also can't lose sight of the fact that all  immunotherapies may be lethal. There is clearly much to be learned.

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

(updated)

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.

"Immune exhaustion"  has been raised as one reason why the immune system fails at combating cancer. Reducing the tumor burden with SBRT has been found to increase immune response in patients with melanoma.

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 June 2022:] Hannan et al. reported on 20 mCRPC patients who received Provenge and SBRT to 1-5 oligometastatic metastases. The combination did not retard progression compared to historical controls.

(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.

(Update 10/6/21) Kwan et al. reported the results of the Phase II ICE-PAC trial combining SBRT of metastases with the immune checkpoint blocker avelumab in 31 mCRPC men in Australia.

• "Disease Control," defined as complete response, partial response, or stable disease, was realized in about half the patients.
• Only 16% suffered serious (Grade 3 or 4) toxicity and only 10% had to discontinue avelumab.
• Response was independent of the number of metastases that were irradiated.

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