New Combination Of Old Drugs Improves Survival In Patients With Prostate Cancer
Adding Zytiga plus prednisolone to standard therapy lengthened survival.
A novel combination of well-known drugs prolongs survival in patients with hormone/castration-sensitive prostate cancer, according to late breaking research presented at the European Society for Medical Oncology annual meeting .
The PEACE-1 and STAMPEDE studies found that the addition of abiraterone acetate plus prednisolone to standard therapy lengthened survival compared to standard therapy alone.
For men with metastatic prostate cancer, androgen deprivation therapy was the standard of care for decades. In 2015, docetaxel was shown to improve survival when added to ADT and in 2017, abiraterone was also shown to improve survival when added to ADT. Until now, though, it was unknown whether one or both agents should be added to ADT to achieve the best outcomes. PEACE-1 found that using three drugs upfront is better than just two in men with metastatic prostate cancer, not only to postpone cancer progression, but also to prolong life. When AAP was added to ADT and docetaxel, men experienced an additional 25% reduction in the risk of death compared to ADT and docetaxel alone.
The trial found that at six years, men who had received standard treatment plus AAP for two years had an improvement in metastasis-free survival from 69% to 82%, an improvement in overall survival from 77% to 86% and an improvement in prostate cancer specific survival from 85% to 93%compared to standard treatment alone.
Hormone Therapy For Prostate Cancer
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Hormone therapy is also called androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cells.
Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgen is made by the testicles, but the adrenal glands as well as the prostate cancer itself, can also make a fair amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.
Steroids For Metastatic Prostate Cancer
Steroids can help to reduce the amount of testosterone made in your adrenal glands or they may help to reduce the side-effects of certain drug treatments.
Side-effects from steroids include an increased appetite and mood changes. They can also cause bone thinning, a higher risk of diabetes, fluid retention, and other body changes. Your doctor will check for these side-effects regularly.
Read more about steroids.
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Taking Aim At An Undruggable Target
Since FOXA1 is transcription factor, it is widely considered to be undruggable. But in this study, we actually found that PARP-2 interacts with FOXA1 and enhances its function. By blocking PARP-2, you can shut down AR signaling, Dr. Jia said.
Drugs called PARP inhibitors have garnered a lot of attention in recent years. They work by preventing cells from utilizing DNA repair pathways, and this prevention leads to cancer cell death. Several of these drugs are already approved for ovarian and breast cancers driven by mutations in DNA repair genes, including BRCA1 and BRCA2. They are also showing promising results for other cancers driven by DNA repair mutations, such as prostate and pancreatic cancer.
However, these drugs largely target PARP-1 instead of PARP-2, said Adam Stuart Kibel, MD, chief of the Brighams Division of Urology and the studys other co-corresponding author. Rather than playing a role in the DNA repair pathway, PARP-2 is a critical component of the AR transcriptional machinery. By finding a way to disrupt FOXA1 function, we now have a therapy that will kill the cancer cell via an alternative mechanism.
Importantly, PARP-2 is found at much higher levels in prostate cancer tumors than in benign prostate tissue, enhancing its appeal as a target.
How Will I Know That My Hormone Therapy Is Working
Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual mans prostate cancer. Therefore, men who take hormone therapy for more than a few months are regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a mans cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a mans prostate cancer has become resistant to the hormone therapy that is currently being used.
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What Is My Outlook
If youre diagnosed with advanced prostate cancer, you may want to know how well your treatment is likely to control your cancer and for how long it will control it. This is sometimes called your outlook or prognosis. But not all men will want to know this.
While it isnt possible to cure advanced prostate cancer, treatments can help keep it under control, often for several years. Treatments will also help manage any symptoms, such as pain.
No one can tell you exactly what your outlook will be, as it will depend on many things such as where the cancer has spread to, how quickly it has spread, and how well you respond to treatment. Some men may not respond well to one treatment, but may respond better to another. And when your first treatment stops working, there are other treatments available to help keep the cancer under control for longer. Speak to your doctor about your own situation and any questions or concerns you have.
Costly Vs Inexpensive Bri
This study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.
The editorialists suggest that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost,” they state.
The two agents differ mechanistically, they add, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.
In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.
International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost ,” the editorialists say.
The dramatically higher cost of denosumab vs zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.
JAMA Netw Open. 2021 4:e2117159, e2116536. Study, Editorial
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Early Versus Delayed Treatment
For men who need hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if its started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.
But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldnt be started until a man has symptoms from the cancer. This issue is being studied.
Good Prostate Cancer Care
Your MDT will be able to recommend what they feel are the best treatment options, but ultimately the decision is yours.
You should be able to talk with a named specialist nurse about treatment options and possible side effects to help you make a decision.
You should also be told about any clinical trials you may be eligible for.
If you have side effects from treatment, you should be referred to specialist services to help stop or ease these side effects.
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Modern Treatment Of Metastatic Prostate Cancer
Henriette Veiby Holm PhD, specialty registrar in surgery and urology at Bærum Hospital. She contributed to the study concept and design, to the literature review and drafting/revision of the manuscript, and has approved the submitted version.
The author has completed the ICMJE form and reports no conflicts of interest.
Alv A. Dahl research advisor and professor emeritus at the University of Oslo. He contributed to the study concept and design, to the revision of the manuscript, and has approved the submitted version.
The author has completed the ICMJE form and reports no conflicts of interest.
National Advisory Unit on Late Effects After Cancer Treatment
Oslo University Hospital, Norwegian Radium Hospital
Olbjørn Harald Klepp specialist in oncology and professor emeritus at the Norwegian University of Science and Technology. He has previously served as head of the oncology departments in Trondheim and in Ålesund. He is a co-author of previous national guidelines, textbook chapters and other publications on prostate cancer. He contributed to the literature review and to drafting/revision of the manuscript and has approved the submitted version.
The author has completed the ICMJE form and reports no conflicts of interest.
Department of Oncology
The author has completed the ICMJE form and reports no conflicts of interest.
National Advisory Unit on Late Effects After Cancer Treatment
Medications For Prostate Cancer
Other names: Cancer, Prostate Carcinoma of Prostate
Prostate cancer is a cancer that occurs in the prostate, which is a small, walnut-sized gland that is located just below the bladder in men and which surrounds the urethra .
Prostate cancer is common, and many men have a slow-growing form of prostate cancer. Death, when it happens, is usually from other causes rather than the cancer itself. However, some prostate cancers are aggressive and can quickly spread outside the confines of the prostate. These are associated with a lower rate of survival.
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What Causes Prostate Cancer
Cancer is the uncontrollable growth of cells. It occurs when a mutation or abnormal change occurs that upsets how our cells multiply and divide. This allows the cell to keep dividing, out-of-control, instead of dying and being replaced by a new cell. Sometimes these out-of-control cells cluster together and form a lump called a tumor. Tumors can form in almost any area of the body.
Most prostate cancers develop from the gland cells in the prostate- these are the cells that make prostate fluid that is added to semen. These are called adenocarcinomas. Other types of cancer that can start in the prostate are rare.
Experts arent sure why some men develop prostate cancer and others dont however, they have identified a few risk factors that make some men more likely to develop the condition. These include:
What Are The Side Effects Of Hormone Therapy For Prostate Cancer
Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:
- loss of interest in sex
Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer Trial 30891. Journal of Clinical Oncology 2006 24:18681876.
Zelefsky MJ, Eastham JA, Sartor AO. Castration-Resistant Prostate Cancer. In: Vincent T. DeVita J, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9e. Philadelphia, PA: Lippincott Williams & Wilkins 2011.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. European Urology 2021 79:150158.
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Targeted Therapy For Prostate Cancer
Targeted therapy is a type of cancer treatment that uses drugs to identify and attack cancer cells while doing little damage to normal cells. These therapies attack the cancer cells’ inner workings the programming that makes them different from normal, healthy cells. Each type of targeted therapy works differently, but they all change the way a cancer cell grows, divides, repairs itself, or interacts with other cells.
Antiandrogens For Prostate Cancer
These prostate cancer drugs work by blocking the effect of testosterone in the body. Antiandrogens are sometimes used in addition to orchiectomy or LHRH analogs.This is due to the fact that the other forms of hormone therapy remove about 90% of testosterone circulating in the body. Antiandrogens may help block the remaining 10% of circulating testosterone. Using antiandrogens with another form of hormone therapy is called combined androgen blockade , or total androgen ablation. Antiandrogens may also be used to combat the symptoms of flare . Some doctors prescribe antiandrogens alone rather than with orchiectomy or LHRH analogs.
Available antiandrogens include abiraterone acetate , apalutamide ,Ã biclutamide , darolutamide ,Ã enzalutamide , flutamide , and nilutamide . Patients take antiandrogens as pills. Diarrhea is the primary side effect when antiandrogens are used as part of combination therapy. Less likely side effects include nausea, liver problems, and fatigue. When antiandrogens are used alone they may cause a reduction in sex drive and impotence.
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Intermittent Versus Continuous Therapy
The common complications of androgen deprivation therapy include sexual dysfunction, mood disturbance, change in body composition and osteoporosis.2,3 In view of these adverse effects intermittent dosing has been considered. This is a period of androgen deprivation therapy followed by a break until disease progression, if a good response was attained. The optimal duration of androgen deprivation therapy is fairly arbitrary as the studies have looked into various periods ranging from three months to three years.
In patients with PSA relapse only , intermittent therapy has been shown to be non-inferior to continuous dosing. There was also a better quality of life with intermittent dosing.4
In patients with objective metastases, intermittent androgen deprivation therapy had numerically worse outcomes than continuous treatment, but the study was statistically inconclusive. There was less sexual dysfunction and better mental health in the intermittent group, but this effect disappeared by 15 months when most people were back on continuous treatment.5 If short-term quality of life is important, even at the risk of possible worse survival, intermittent therapy is a reasonable approach.
Chemo Drugs Used To Treat Prostate Cancer
For prostate cancer, chemo drugs are typically used one at a time. Some of the chemo drugs used to treat prostate cancer include:
- Docetaxel
- Mitoxantrone
- Estramustine
In most cases, the first chemo drug given is docetaxel, combined with the steroid drug prednisone. If this does not work , cabazitaxel is often the next chemo drug tried .
Docetaxel and cabazitaxel have been shown to help men live longer, on average, than older chemo drugs. They may slow the cancers growth and also reduce symptoms, resulting in a better quality of life. Still, chemo is very unlikely to cure prostate cancer.
Other chemo drugs being studied for use in prostate cancer include carboplatin, oxaliplatin, and cisplatin.
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How Does Hormone Therapy Work Against Prostate Cancer
Early in their development, prostate cancers need androgens to grow. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of such prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive.
Most prostate cancers eventually stop responding to hormone therapy and become castration resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.
How Is Prostate Cancer Treated
Treatment for prostate cancer depends upon the stage of the prostate cancer and an understanding of the pros and cons of treatment. Treatment options include:
- Watchful waiting. No active treatment is started. This may be appropriate for older men with other serious medical conditions
- Active watching. May involve regular PSA tests and prostate biopsies
- Radiation
- Brachytherapy. Small radioactive pellets are placed permanently into the prostate gland
- Surgery
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What Happens If My Cancer Starts To Grow Again
Your first treatment may help keep your cancer under control. But over time, the cancer may change and it may start to grow again.
You will usually stay on your first type of hormone therapy, even if its not working so well. This is because it will still help to keep the amount of testosterone in your body low. But there are other treatments that you can have alongside your usual treatment, to help control the cancer and manage any symptoms. Other treatments include:
Which treatments are suitable for me?
Which treatments are suitable for you will depend on many things, including your general health, how your cancer responds to treatment, and which treatments youve already had. Talk to your doctor or nurse about your own situation, or speak to our Specialist Nurses.
Endocrine Therapy And Prostate Cancer
Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Hormone therapy, known as androgen ablation or androgen suppression therapy, is the main treatment for advanced prostate cancer. It is the first line of treatment for metastatic prostate cancer.
In many patients, endocrine therapy provides temporary relief of symptoms of advanced prostate cancer. Endocrine therapy may reduce tumor size and levels of prostate specific antigen in most men. PSA is a substance produced by the prostate gland that, when present in excess amounts, signals the presence of prostate cancer.
However, hormone therapy is not without side effects. Some of the more serious side effects include loss of sex drive, impotence, weakened bones , and heart problems.
Eventually, most patients with advanced prostate cancer stop responding to hormone therapy. Doctors call this castrate-resistant prostate cancer.
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