Prednisone to Blame for ERA 223 Trial Failure?

[pjoshea13]

Further to my recent post:

"Radium-223 + Abiraterone & prednisone/prednisolone" [1]

...

"Prednisone to Blame for ERA 223 Trial Failure?" [2] [3]

"Bone loss resulting from excessive use of prednisone with abiraterone and radium-223 may explain the higher risk of fragility fractures among men in the ERA clinical trial, according to an editorial published in European Urology.

“This editorial was written in order to provide potential explanations on why the association of radium-223 with abiraterone plus prednisone unexpectedly failed to meet its primary endpoint, the prevention of skeletal-related events,” corresponding author Alfredo Berruti, MD, professor of medical oncology at the University of Brescia in Italy, told Renal & Urology News."

"Glucocorticoid-induced inhibition of bone formation involves multiple pathways, resulting in strong suppression of osteoblast differentiation, maturation, and activity, Dr Berruti and his colleagues wrote. He and his colleagues say they believe the trial findings, which were presented at the 2018 congress of the European Society for Medical Oncology, were primarily due to a negative interaction between radium-223 and prednisone leading to a synergistic inhibition on osteoblast activity and the consequent bone coupling derangement favoring the prevalence of osteoclast activity. “Prednisone supplementation needs to be administered to patients during abiraterone therapy in order to inhibit ACTH [adrenocorticotropic hormone] increase and the consequent mineral corticoid excess; however, the prednisone dose administered in the ERA223 trial (10 mg daily) is excessive,” Dr. Berruti said. “We felt it important to share our point of view in the scientific community since the consequence of this trial is a sort of pessimism linked to radium-223 administration, and we strongly believe the drug still remains an important therapeutic option in the management of castration resistant prostate cancer patients.”

"The ERA 223 trial was a randomized phase 3 study that enrolled 806 men with asymptomatic or mildly symptomatic men with chemotherapy-naïve castration-resistant prostate cancer (CRPC) and bone metastases (more than 2 bone metastatic lesions). Patients received a combination of standard-dose abiraterone (1000 mg daily) combined with 5 mg of prednisone (twice daily) and radium-223 or placebo.

"Previous studies have shown that abiraterone and prednisone/prednisolone improves progression-free survival (PFS) and overall survival (OS) in men with metastatic CRPC (mCRPC). In addition, data have shown that use of radium-223 is associated with increased OS and a decreased risk of symptomatic skeletal events (SSEs) in men with mCRPC and bone metastases.

"The ERA 223 trial, however, was unblinded early after investigators observed more fractures and deaths among patients in the radium-223 group. The median time to SSEs in the radium-223 arm was 22.3 months vs 26.0 months in the placebo arm, and the median OS was 30.7 months vs 33.3 months in the placebo arm. Results showed that 29% of men who received radium-223 experienced fractures compared with 11% of the placebo arm. Use of bisphosphonates or denosumab was associated with lower fracture rates in both treatment groups.

"Based on the study findings, the investigators said they do not recommend radium-223 in combination with abiraterone plus prednisone.

“The results of the ERA trial suggest that the concomitant administration of glucocorticoids is detrimental and should be in principle avoided,” Dr Berruti said. “However, if deemed necessary by the clinicians, concomitant administration of bone resorption inhibitors (denosumab and bisphosphonates) are needed to counteract the increased risk of fragility skeletal fractures.”

"The randomized phase 3 ALSYMPCA trial showed that administration of radium-223 was associated with a significant delay in time to first SSE and significant improvement in OS compared with placebo, regardless of previous docetaxel use.

"Michael J. Morris, MD, clinical director of the Genitourinary Medical Oncology Service and head of the Prostate Cancer Section at Memorial Sloan Kettering Cancer Center in New York, said clinicians have feel their way when deciding how much prednisone to use. “Prednisone mitigates important side effects of abiraterone, such as hypertension, hypokalemia, and edema,” Dr Morris said. “Most practitioners try to find the right balance of steroid use with each patient, and the right dose for a given patient is frequently individualized.”

"The editorial raises good points, he said, but more research is warranted to better understand the mechanisms involved when combining abiraterone and prednisone with radium-223. “It could be the combination of these drugs has biological effects that occur in the bone that we don't know about. Everyone is struggling to come up with an explanation, and this is just one hypothesis,” he said.

"Howard Sandler, MD, a professor and chair of radiation oncology at Cedars-Sinai Medical Center in Los Angeles, noted that the ongoing Phase III Radium-223 mCRPC-PEACE III (PEACE III) trial (NCT02194842) could provide additional insight into the use of radium-223. The randomized open-label trial is assessing whether upfront use of a combination of enzalutamide plus radium-223 improves radiographic PFS compared with enzalutamide alone in men with asymptomatic or mildly symptomatic CRPC patients with bone metastases.

“More studies are always helpful, and some are underway,” Dr Sandler said. “I'm not involved in any guideline panels for prostate cancer metastatic to bone, but I'm sure guidelines panels would suggest caution using radium-223 and abiraterone/prednisone at the present time.” He noted, however, that the original study showing a benefit with the use of radiation in the form of radium-223 as a single agent still stands as a positive trial with a survival benefit and very little in the way of side effects."

-Patrick

[1] healthunlocked.com/advanced...

[2] renalandurologynews.com/pro...

[3] europeanurology.com/article...

[NPfisherman]

Thanks for posting...I believe the OS survival rate being lower in the radium- 223 arm was related to the fracture component also--It is well known that a hip fracture in the elderly increases your risk of dying significantly... As they said in this article--people were on prednisone 10 mg with zytiga and radium-223....unclear why....I take 5 mg prednisone with zytiga...

Have a great weekend,

Fish

[George71 in reply to NPfisherman]

I wonder if taking Xtandi with Radium 223 would be a better choice -- I think Xtandi doesn't require prednisone -- ?

[NPfisherman in reply to George71]

Logically, that makes total sense....I am thinking yeah... They are looking at it :

onclive.com/web-exclusives/...

I bet there may be a phase 2 happening or planned....

It just makes sense to get the tumor burden down asap... Combos of 2 and 3 drugs will be the new standard with this disease.... especially, as more drugs get approved...that and combo therapies....nanoparticles with abiraterone or enzalutamide or apalutamide, and stereotactic radiation, chemo, immunotherapy--in some type of series based on genetic mapping of the cancer... it is why I am excited about the Match trial--Targeted Therapy based on gene mapping... In 5 years, they have made more advances than in the past 50.... the DNA model has helped....

Have a great day,

Fish

[tarhoosier in reply to NPfisherman]

With the newer generation of -lutamides, Enza-, Apa, Daro- (soon). I think Zytiga will become a later choice for doctors and patients. Those unsuitable for -lutamides, or others may choose Zytiga but the requirement for prednisone and the dosing requirements around food mean that for the older men this is aimed for, zytiga will decline in use.

[NPfisherman in reply to tarhoosier]

Respectfully, I disagree because of STAMPEDE results especially in low volume disease/ oligometastatic disease, I believe Zytiga will be first line in that situation..

ascopost.com/News/55699

Another reason is price--zytiga--now generic is around $3,200 a month vs the lutamides at $11,000 per month or greater... Let us not forget that the insurance companies also play a role in this arena and that also points towards zytiga. We must wait to see as initial results on Darolutamide look really good...( See TNCanuck's post a day or so ago)....

For me, I am just happy to see the advances George71 posted about TOOKAD, nanoparticles, etc...I watch the trials on TAS3681 and TRC253--both for wild/mutated AR--if they are successful, then castrate resistance may be eliminated or pushed back--add on another 4-5 years to OS...end result--a chronic illness instead of a short term death sentence...

I am patiently waiting for the ACS to list their new survival rate for APC....the last was 30% for 5 year survival and 4% for 10 years using data from 2010-2014... That data didn't really include abiraterone--approved Dec 2012-- I am thinking those numbers have changed dramatically...

All the best,

Fish

[pjoshea13 in reply to tarhoosier]

We are used to thinking in terms of either/or, but the logical end point for androgen receptor [AR] axis treatments, is a combination of androgen elimination & AR antagonist.

-Patrick

[NPfisherman in reply to pjoshea13]

What are your thoughts on TAS3681 and TRC253--both for wild/mutated AR ?? Do you think this holds as much value as I do, in regards to blocking castrate resistance and turning APC into more of a chronic disease? I think if these work it may add significant additional time to patients with mCRPC...

All the nest,

Fish

[pjoshea13 in reply to NPfisherman]

Fish,

TAS3681 and/or TRC253 might turn out to be very important for CRPC men - or where AR changes have already occurred due to ADT (pre-CRPC), but for a newly-diagnosed man with wild-type AR? I don't know enough about them to comment.

I suppose that they would prevent the emergence of AR-V7, etc. I'm wondering what resistant AR would look like.

-Patrick

[NPfisherman in reply to pjoshea13]

Patrick,

I kind of think of these as next generation AR blockers going the next step--

Here is some info on TAS3681:

mct.aacrjournals.org/conten...

In prostate cancer cells which express full-length AR and splice variant AR-v7, TAS3681 suppressed AR-v7 target gene expression through downregulation of AR-v7 occupancy at the enhancer. Moreover, TAS3681 reduced expression of c-Myc, critical driver of androgen-independent mechanisms of prostate cancer progression, via AR downregulation activity. In addition, real-time PCR assay showed the suppression of c-Myc and c-Myc target gene mRNA levels by TAS3681 but not by enzalutamide.

Some info on TRC 253:

TRC253 is a novel, orally bioavailable small molecule discovered and developed by Janssen that is a potent, high affinity competitive inhibitor of the androgen receptor (AR). TRC253 is also a pan-inhibitor of multiple AR mutations, including the F876L mutation, and is under development for the treatment of men with prostate cancer. The AR F876L mutation results in an alteration in the ligand binding domain that confers resistance to current AR inhibitors. TRACON initiated clinical development of TRC253 in May 2017.

TRC253 is intended to address resistance mechanisms to current AR inhibitors by specifically targeting mutations in the AR ligand binding domain. TRC253 also potently inhibits signalling through the wild type AR. These susceptible AR mutations have been identified using circulating tumor DNA assays, potentially allowing for selected patient biomarker-directed therapy.

If these work, it will address areas where drugs like enzalutamide fail, and possibly a 2 drug combo could make ADT therapy continue to work, thus buying patients more time. Here's hoping they work....

Fish