Treatment To Lower Androgen Levels From Other Parts Of The Body
LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Some drugs can block the formation of androgens made by these cells.
Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced prostate cancer that is either:
This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone needs to be taken during treatment as well to avoid certain side effects.
Ketoconazole , first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. Its most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.
Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid .
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.
Hormone Therapy Plus Zoledronic Acid
Zoledronic acid was FDA-approved in 2002 in an attempt to decrease morbidity from bone metastases in bone-tropic diseases including prostate cancer. In STAMPEDE, 593 patients were randomized to this arm between October 2005 and March 2013. Zoledronic acid was administered over six 3-weekly cycles, then every 4 weeks for up to 2 years. Preliminary analyses for FFS at predetermined intervals failed to show an effect from zoledronic acid added to standard ADT, irrespective of docetaxel use . In addition, the OS hazard ratio was 0.94 with no obvious benefit from Zoledronic acid in any of the subgroup analyses including those with metastatic disease. There also appeared to be no beneficial effect on skeletal-related events .
The role of zoledronic acid or other bisphosphonates in the context of advanced prostate cancer has been examined in several other trials and in an accompanying meta-analysis published at same time of the results noted above . The results of STAMPEDE mirrored those of the earlier findings from CALGB-90202, which was also stopped early due to lack of an effect . In that study, zoledronic acid provided no OS benefit and no improvement in SREs when added to ADT in men with bone-metastatic hormone-sensitive prostate cancer.
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Uncertainty About Whether It Would Work For All Men
Abiraterone is a new type of hormone treatment that is given to men with advanced prostate cancer once their cancer has become resistant to ADT. Today’s results suggest giving abiraterone earlier in the treatment pathway could increase how effective it is. However, it’s not clear how much this would benefit men in reality, as clinical practice for treating advanced prostate cancer has changed since the trial began.
Following the STAMPEDE trial results from 2015, which showed giving the chemotherapy drug, docetaxel, at the same time as ADT helped men survive for an average of 15 months longer than ADT alone, earlier docetaxel quickly became the standard treatment option for men with advanced prostate cancer on the NHS.
As docetaxel and abiraterone have not been compared side-by-side, we can’t say yet which is better. Even more importantly, we need a way to find out if they will work differently in different men, or if they might work even better together.
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 Rosenbergs 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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Is There A Rationale For Genetic Workups Before Treatment
Panellists answered this question from the floor, with Tombal explaining that current guidelines advise genetic workup in patients with a family history of cancer, with newly-diagnosed metastatic cancer, and in patients with intraductal and cribriform prostate cancer.
Patients with newly-diagnosed metastatic cancer found to have certain genetic mutations could qualify for treatment with a class of drugs called poly polymerase inhibitors that cause cell death. Otherwise, genetic workups are more for the purposes of genetic counselling, and have broader implications for research, explained Tombal.
Adding Abiraterone To Standard Therapy Helps People With Metastatic Prostate Cancer To Live Longer
Adding the drug abiraterone to standard hormone therapy helps people with prostate cancer that has spread to other parts of the body to live longer. Results from the STAMPEDE trial were presented at the European Society for Medical Oncology Congress in Paris last week. For more on this, please click on the following link to the UCL News feed:
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Stage 3 treatment. Stage 3 prostatecancer involves a tumor thats grown and is locally advanced. Stage 3 is also divided into 3A, 3B and 3C. The higher the stage, the more its spread to nearby structures such as the seminal vesicles, the bladder and rectum. In stage 3, cancer cells look different from healthy prostate cells.
TUESDAY, Jan. 18, 2022 Advanced forms of hormone therapy are very effective at keeping prostatecancer in check, but they also can double a mans risk of falling into depression,.
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Mens Health Newtreatment approved for late-stage prostatecancer April 7, 2022 By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases In late March, the FDA approved a new therapy for advanced prostatecancer that is metastasizing, or spreading, in the body.
The Role Of The Urologist
Management of mHSPC has traditionally been in the domain of the urologist. Since ADT was standardised as a first-line option for these patients many years ago, it has been the urologist who has been the primary specialist overseeing their care until the emergence of castration-resistance. However, the upfront use of Docetaxel chemotherapy and ARPIs has led to changes in patterns of care, with medical oncologists playing an increasing role in the primary management of mHSPC. Whilst Docetaxel is most often administered by medical oncologists, it is also administered by urologists in some countries, especially in the Asia-Pacific region . The increasing role for well tolerated oral ARPIs combined with ADT for mHSPC, also means that urologists can continue to play a key role in the management of mHSPC, provided they are willing to become facile with the safe use and monitoring of these agents . Ultimately, these patients are best managed in multidisciplinary teams, taking into account patient and disease factors, as well as access and affordability issues .
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The Stampede Trial: Paradigm
Bradley C. Carthon1, Emmanuel S. Antonarakis2
1 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , , USA
: James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer : survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016 387:1163-77.
Keywords: Androgen deprivation docetaxel stampede zoledronic acid
Submitted Jul 22, 2016. Accepted for publication Aug 02, 2016.
Imaging And The Treatment Of Non
Tombal began the panel discussion by asking about the role of modern imaging in treatment decisions for patients with nmCRPC.
Gratzke and BÃ¶gemann agreed that a negative prostate-specific membrane antigen PET scan is not a reason to delay ARi treatment in a patient with nmCRPC who is in good shape, but shows a PSADT of 7 months.
Why would you wait if you had a drug that is able to prolong survival and metastasis-free survival with a good quality of life? said Gratzke. There is no real, good argument to do so.
A PSADT of 7 months means there is a high risk of developing metastasis within a short period of time, added BÃ¶gemann. So, even if the PSMA PET scan is negative, why wait, he agreed.
Tombal provided another example of a patient who had undergone prostatectomy and radiotherapy following rapid progression. Initially, their PSMA PET scan was negative and so ARi treatment was deferred. However, 3 months later, their PSA had doubled and a subsequent PSMA PET scan showed a large metastasis on the hip. The patients doctors opted for radiation therapy only. Tombal asked if the panel agreed with this approach.
When there is systemic disease, there is a very good rationale for offering systemic treatment, Gatzke responded. Radiation is still important, however, especially if the patient is experiencing pain or has a risk of fracture.
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Innovation In Trial Design
Within the group, the researchers developed a plan to implement an innovative trial design it was a multi-arm, multi-stage design that would allow them to test a greater number of treatments faster and more efficiently. The STAMPEDE trial would have only one control arm, against which all other treatments could be tested, and there were analysis periods built in so that insufficiently active treatments could be stopped rather than continued to the end of the trial.
Table: Treatment comparisons investigated at times across the STAMPEDE trial
|Standard of care plus zoledronic acid|
|Standard of care plus docetaxel chemotherapy|
|Standard of care plus celecoxib|
|Standard of care plus zoledronic acid + docetaxel|
|Standard of care plus zoledronic acid + celecoxib|
|Standard of care plus abiraterone|
|Standard of care plus abiraterone + enzalutamide|
|Standard of care plus the provision of prostate radiotherapy for men with metastases|
|Standard of care plus metformin|
|Standard of care plus transdermal oestradiol|
*Standard of care was long-term hormone therapy, plus radiotherapy if possible, in non-metastatic patients. The standard has been updated over time to include docetaxel or abiraterone, and radiotherapy across all patients
Improving How Long Patients Live
The ENZAMET trialfunded in part by the drugs manufacturer, Astellas Pharma, as well as government health agencies in Canada and Australiaenrolled more than 1,100 men with hormone-sensitive metastatic prostate cancer. The men were randomly assigned to ADT combined with enzalutamide or with any of three other androgen-blocking drugs.
At a median follow-up of nearly 3 years, men who received ADT plus enzalutamide had a 33% reduced risk of death, with 80% still alive compared with 72% of men treated with ADT plus another antiandrogen drug, reported the trials lead investigator, Christopher Sweeney, M.B.B.S., of the Dana-Farber Cancer Institute.
Men in the enzalutamide group also had better clinical progression-free survival , which the research team defined as the time until the return of disease-related symptoms, the detection of new metastases on imaging scans, or the initiation of another cancer treatment for prostate cancer, whichever came first. At 3 years, 63% of men in the enzalutamide group were alive without clinical progression of their disease, compared with 33% in the standard treatment group.
Although enzalutamide appeared to be effective regardless of whether men had high- or low-volume disease, one apparent differentiating factor was planned early treatment with docetaxel. Nearly half of the men in both treatment groups received early treatment with docetaxel and, for those men, enzalutamide was not associated with longer overall survival.
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Primary And Secondary Outcomes
The primary efficacy outcome measure was OS, defined as time from randomisation to death from any cause. Secondary outcomes for this long-term efficacy analysis included local interventionfree survival consisting of time from randomisation to the first report on case report forms of TURP, ureteric stent, surgery for bowel obstruction, urinary catheter, nephrostomy, colostomy, death from prostate cancerand symptomatic local event-free survival , comprising any of these LIFS events or acute kidney injury, urinary tract infection, or urinary tract obstruction. Cause of death was determined by the site investigator, with some cases reclassified as prostate cancer death according to predefined criteria which suggested this to be the likely cause. Patients without the event of interest were censored at the time last known to be event free. QoL analyses focused on Global QoL % and QLQ-30 Summary Score %, as derived from patient reports at scheduled assessment time points in the first 2 years after randomisation .
Prioritizing Qol Surveys In Clinical Trials Gives Insights Into Qol Impacts Of Life
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The treatment landscape for men with metastatic hormone-sensitive prostate cancer has changed dramatically over the last 5 years, with abiraterone and a number of new therapies used in combination with androgen-deprivation therapy being approved.
Data from the STAMPEDE trial and others have demonstrated that treatment with docetaxel or abiraterone started concurrently with long-term ADT prolongs survival when compared with ADT alone. As a result, patient-reported quality of life between these treatments may guide treatment choice, and the impact of additional treatment with docetaxel or abiraterone on QOL has not been directly compared.
The STAMPEDE trial is a phase III multiarm, multistage platform trial assessing different treatment regimes given alone or in combination with long-term ADT. In a study recently published in the Journal of Clinical Oncology, Rush and colleagues assessed QOL in 515 men enrolled in STAMPEDE randomized to receive docetaxel or abiraterone concurrently with ADT over a 2-year follow-up period. QOL was measured using the EORTC QLQ-C30 questionnaire with the prostate cancer-specific PR25 module, and the primary outcome was a difference in QOL with a pre-defined criterion for a clinically meaningful difference of > 4 points.
Read the study here and an interview about it here.
Bradley C. Carthon1, Emmanuel S. Antonarakis2
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Further Research And Trial Results To Come
It’s important we fully understand how earlier use of abiraterone will benefit men with advanced prostate cancer and if this outweighs the side effects from the drug. Severe side effects, such as hypertension and liver problems, were reported by 41% of men taking abiraterone in the STAMPEDE trial, compared to just 29% in the control group receiving just ADT.
The findings were published in the New England Journal of Medicine and we’re expecting results from another similar trial, known as LATITUDE, to be announced on Sunday that was conducted by the pharmaceutical company that owns abiraterone. We’ll have more analysis of these and the STAMPEDE trial’s results early next week.
How Psma Lights Up Cancer Cells
In 2021, the U.S. Food and Drug Administration issued national approval to two new prostate cancer imaging tests based on similar technology. On a PET scan, the test lights up the cancerous cells that would otherwise be hidden, enabling doctors to precisely target treatment.
Both advances in imaging and therapy rely on targeting PSMA, which is not found on most normal cells but is overexpressed in cancer cells, especially those that have spread. The PSMA molecule was cloned at MSK in the early 1990s.
The Molecular Imaging and Therapy Service, led by Heiko Schöder, played a key role in the development and testing of a slightly different PSMA-directed imaging technology at MSK.
This advance is the result of years of work by the community of physicians promoting the use of PSMA agents, Dr. Schöder says. Its gratifying to see a collaborative effort result in a breakthrough that has the potential to make a difference for so many patients with advanced prostate cancer.
Before receiving the therapy, patients in the VISION trial were scanned with PSMA-directed PET imaging to make sure enough PSMA was present in the cells to make them likely to respond to the treatment. If so, they received the radioactive drug by injection over four to six sessions, spaced six weeks apart.
As a next step, Dr. Morris and colleagues are looking into using the PSMA-directed therapy earlier rather than only after the prostate cancer has spread.
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