#zytiga

 Findings of a phase 3 clinical trial published in The Lancet Oncology on September 30, 2021, by an international research team led by Dr. Fred Saad, a researcher at the CHUM Research Centre, a Université de Montréal professor and the holder of the Raymond Garneau Chair in Prostate Cancer Research indicate that the combination of Zytiga (abiraterone), prednisone and Erleada (apalutamide) can delay the progression of metastatic castrate-resistant prostate cancer. 

The trial was a collaboration with 167 hospitals in 17 countries. The study, called ACIS, identified for the first time a combination of three drugs that slowed the progression of metastases by more than seven months. This finding is a significant therapeutic breakthrough for treating advanced prostate cancer. 

The trial evaluated 982 men between the end of 2014 and the middle of 2016 and divided them randomly into two groups (randomized, double-blind trial). Of the volunteers, 492 received apalutamide (an anti-androgen) combined with abiraterone (an androgen synthesis inhibitor) and prednisone (an anti-inflammatory drug). 

The control group of 490 men received only abiraterone and prednisone.  This well-tolerated therapeutic trio was administered to men with metastatic castration-resistant prostate cancer. Prostate cancer is considered castration-resistant when cancer progresses despite hormone therapy. 

By following the progression of the cancer through radiologic scans, the researchers were able to show that the men in the triple treatment group lived 24 months (median) without signs of disease progression, compared to 16.6 months for those in the standard of care control group. 

The researchers have suggested that additional studies will help to accurately identify the sub-categories of men who would most benefit from this combination of drugs. 

At Cancer ABCs, we acknowledge the great value that the many current, ongoing clinical trials of combinations of approved drugs can bring to our treatment protocol. However, we suggest that, in addition to combination studies, there need to be other studies that evaluate the survival benefit of sequencing the same drugs and comparing these results to the combination trials. Included in the comparison, we wish to see an evaluation of patient-reported side effects between the sequenced and combination trials.

 REFERENCES 

Since the approval of the second generation LHRH Therapies like Abiraterone acetate (Zytiga) plus prednisone (AA+P), many men we talk with at Cancer ABCs have been asking us if it is necessary to continue taking first-line ADT, or hormone therapy.  

Hormone therapy, ADT, causes castration or removing the androgens such as testosterone from the body. It comes with many significant adverse side effects. These side effects include loss of libido, loss of muscle, and bone mass, causing an increased risk of fractures, hot flashes, cardiovascular complications, metabolic complications like diabetes, etc. Given the host of ADT's potential adverse complications, can stopping ADT improve the quality of life while not compromising the prostate cancer treatment?

In an abstract, 5046, presented at the 2019 Virtual ASCO Meeting, this question was asked. The abstract provided us with a summation from the SPARE-trial (NCT02077634); CH Ohlmann, C Ruessel, R Zillman, et al. .It asked what would happen if men with metastatic castrate resistant prostate cancer who were chemotherapy naïve, or who never have had chemotherapy to treat their prostate cancer, but who were taking Zytiga and prednisone stop hormone therapy or ADT.  

The SPARE-trial was an exploratory phase II study, including 67 men. In the trial, the subject men were randomized to receive continued ADT plus Zytiga and prednisone or Zytiga plus prednisone alone (without ADT). The goal was to determine the value of continuing ADT.   

The researchers found that in all men who received Zytiga plus prednisone and ADT, their median testosterone levels remained below castrate levels throughout treatment.

In 18% of the men who only received Zytiga and prednisone (no ADT), their testosterone levels increased above castrate levels within 28 days after their ADT treatment was stopped.

They also found that the median treatment duration was shorter in the men receiving Zytiga plus prednisone and ADT.

The researchers concluded that ADT might not be necessary for men receiving Zytiga and prednisone. However, some men may experience a rapid increase in serum testosterone levels, warrant close monitoring, and adding back ADT.

This research is not conclusive and only evaluated the possibility of halting ADT while taking Zytiga and prednisone. It did not consider stopping ADT with any other second-generation hormone manipulations like Xtandi or Darolutamide.  

It also was a small study that needs to be replicated at a larger scale. This study did not evaluate survival differences between the men who stopped ADT and those who continued ADT while on Zytiga and Prednisone.  

It also did not evaluate what differences the men experienced in their quality of life. 

CAUTION

Under no circumstances should you stop your primary ADT treatment without a careful conversation and your medical oncologist's agreement. 

If you, along with your oncologist, decide to stop ADT while taking Zytiga and prednisone, you and your doctor must develop and execute a plan to AGGRESSIVELY AND CONTINUOUSLY monitor your serum testosterone levels.  

Since the approval of the second generation LHRH Therapies like Abiraterone acetate (Zytiga) plus prednisone (AA+P), many men we talk with at Cancer ABCs have been asking us if it is vital to continue taking first-line ADT (hormone therapy).  

ADT, which causes castration, or the removal of androgens such as testosterone from the body, comes with many significant adverse side effects. These side effects include loss of libido, loss of bone mass, causing an increased risk of fractures, hot flashes, cardiovascular complications, metabolic complications like diabetes, etc. Given the host of ADT's potential complications, can stopping ADT improve the quality of life while not compromising the prostate cancer treatment?

In an abstract, 5046, presented at the 2019 Virtual ASCO Meeting, this question was asked. The abstract provided us with a summation from the SPARE-trial (NCT02077634); CH Ohlmann, C Ruessel, R Zillman, et al. asked what would happen if men with metastatic castrate resistant prostate cancer who were chemotherapy naive and who were taking Zytiga stopped first line ADT.  

The SPARE-trial was an exploratory phase II study, including 67 men. In the trial, the subject men were randomized to receive continued ADT plus Zytiga and prednisone or Zytiga plus prednisone alone(without ADT) to determine the value of continuing ADT.    

The researchers found that in all men who received Zytiga plus prednisone and ADT, their median testosterone levels remained below castrate levels throughout treatment.

In 18% of the men who only received Zytiga and prednisone (no ADT), their testosterone levels increased above castrate levels 28 days after treatment cessation.

They also found that the median treatment duration was shorter in the men receiving Zytiga plus prednisone and ADT.

The researchers concluded that ADT may not be necessary for men receiving Zytiga and prednisone; however, some men may experience a rapid increase of serum testosterone levels, warranting close monitoring and adding back ADT.

This research is not conclusive and only evaluated the possibility of halting ADT while taking Zytiga and prednisone. It did not evaluate stopping ADT with any other second-generation hormone manipulations like Xtandi or Darolutamide.  

CAUTION

A post hoc analysis of two randomized clinical trials shows some evidence that taking statins and vitamin D supplements might reduce the risk of death in men who have castrate resistant prostate cancer (CRPC) who are also taking the drug Zytiga (abiraterone acetate or AA) with prednisone. 

There have been observational studies reporting that adding statins to Zytiga and prednisone may boost the antitumor activity of the Zytiga, possibly improving the Zytiga’s efficacy. Conclusions about adding vitamin D are less clear, but a possible benefit has been described in other literature

Researchers performed a post hoc analysis of individual patient data from two randomized clinical trials of men who had castrate resistant prostate cancer and who took Zytiga with prednisone and/or statins or vitamin D.  

In the COU-AA-301 trial, the use of Zytiga with statin and vitamin D reduced the risk of death by 38% (p = 0.0007) while Zytiga alone was associated with a decrease of 10% (p = 0.025), compared to prednisone alone. 

In the COU-AA-302 trial, the use of Zytiga plus statin plus vitamin D was associated with a reduced risk of death of 26% (p = 0.0054). 

In this data analysis from two prospective randomized clinical trials, statin and vitamin D use was associated with superior overall survival in men with metastatic CRPC who were treated with Zytiga and prednisone. Cancer ABCs believe that these data support asking your doctor if you should be adding a statin and or vitamin D to your Zytiga treatment protocol. 

pubmed.ncbi.nlm.nih.gov/321...

A Post Hoc Analysis of Two Randomized Clinical Trials

Observational studies have reported that adding statins to Zytiga (abiraterone acetate or AA) and prednisone may boost the antitumor activity of Zytiga, possibly improving the Zytiga’s efficacy. Conclusions about adding vitamin D are less clear, but a possible benefit has been described in other literature.

Researchers performed a post hoc analysis of individual patient data from two randomized clinical trials of men who had castrate resistant prostate cancer and who took Zytiga with prednisone and/or statins or vitamin D.  

In the COU-AA-301 trial, the use of Zytiga with statin and vitamin D reduced the risk of death by 38% (p = 0.0007) while Zytiga alone was associated with a decrease of 10% (p = 0.025), compared to prednisone alone. 

In the COU-AA-302 trial, the use of Zytiga plus statin plus vitamin D was associated with a reduced risk of death of 26% (p = 0.0054). 

In this data analysis from two prospective randomized clinical trials, statin and vitamin D use was associated with superior overall survival in men with metastatic CRPC who were treated with Zytiga and prednisone. Cancer ABCs believe that these data support asking your doctor if you should be adding a statin and or vitamin D to your Zytiga treatment protocol. 

 pubmed.ncbi.nlm.nih.gov/321...

There was a small clinical trial, by Mark Ratain, M.D., of the University of Chicago, that suggests that it is possible to take a lower dose of Zytiga (abiraterone) along with a low-fat breakfast and achieve a response similar to the one we would expect to see with a full dose on an empty stomach.  

However, the trial does not tell us, if over the long term, taking the lower dose with food will affect the survival advantage that the higher dose offers.   

Since there is growing concern about the increasing cost of all cancer drugs, including Zytiga, the trial’s findings raise the possibility that something as simple as taking food with Zytiga may help to address this economic issue.

In the trial, subjects took one-quarter of the customarily prescribed dose of Zytiga along with food.  They found that with food these subjects had a similar reduction in their prostate-specific antigen (PSA) levels as did the men who took the full dose on an empty stomach. 

According to William Figg, Sr., Pharm.D., of NCI's Center for Cancer Research, an investigator on the study, although it is effective in slowing the progression of metastatic cancer, abiraterone is one of the most expensive drugs on the market.  “We’re trying to find ways to offset the exorbitant cost of these cancer drugs, and this is one potential approach,” Dr. Figg said.

Many drugs that are given by mouth have a food effect: when a medication is taken with a meal instead of on an empty stomach, the body tends to absorb more of it. This effect is because the fat molecules found in food carry the drug more efficiently through the stomach and intestines, so less of the drug is needed when taken with food to obtain the same concentration in the bloodstream.

It is standard procedure to test drugs with a strong food effect in a way that intentionally diminishes the impact. Testing a drug on an empty stomach is done to reduce the potential variability in dose between participants that could arise due to what types of and how much food different people eat.

 The food effect of Zytiga has long been recognized, the large clinical trials that led to the drug’s approval required that participants take it on an empty stomach to mitigate the food concern. As a result, the drug’s label directs patients to take it without food.

In both the food and nonfood groups, men lived for an average of about nine months without their disease progressing.

More extensive studies are needed to measure whether the effects of abiraterone can be maintained in the long term when given at a reduced dose with food, as well as evaluating the result of the reduced dose might have on survival.

In an editorial that accompanied the trial results, Jill Kolesar, Pharm.D., of the University of Kentucky, and Glenn Liu, M.D., of the University of Wisconsin, cautioned doctors, patients, and insurance providers against making dosing decisions based on a small trial with limited follow-up.