Castrate Resistant Prostate Cancer
Eventually, almost all metastatic prostate cancers become resistant to androgen ablation. In patients with castrate serum testosterone levels , castrate-resistant prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from computed tomography scan and/or bone scan, bone pain, or obstructive voiding symptoms.
Rarely, a rise in PSA may reflect failure of LHRH treatment to control testosterone secretion, rather than the development of castrate-resistant disease. Therefore, the testosterone level should be measured when the PSA rises. If the serum testosterone level exceeds castrate levels, changing the antiandrogen therapy may drop the PSA and delay the need for other therapy.
Prior to the development of the most recent therapies, the median time to symptomatic progression after a rise in the PSA level of more than 4 ng/mL was approximately 6-8 months, with a median time to death of 12-18 months. Since then, however, the latter figure has increased.
Little information is available about the impact of maintaining hormone suppression when androgen-independent progression occurs, but the general consensus among specialists is that the treatment should continue. The reasoning is that tumor cells are still hormone sensitive and may grow faster if the testosterone is permitted to rise.
Mutational And Genetic Testing In Mcrpc
All cancers, including prostate cancer, arise because of genetic mutations in cells. The first type mutations to be appreciated as causative in driving mCRPC were in genes involved in repair of damaged DNA. These mutations, often hereditary, were identified long ago as predisposing to the development of breast and ovarian cancers in women.
In prostate cancer, mutations in one of these DNA-repair genes are found mostly in late-stage prostate cancer in about 12% to 20% of patients. These mutations predict whether treatment with drugs known as PARP inhibitors might be effective. The FDA has already approved two drugs in this category: olaparib and rucaparib . New clinical guidelines now dictate testing for these mutations in tumors of mCRCP patients.
A recent study reported that men with deficiencies in one of 13 genes related to DNA damage repair had a higher response rate and a longer progression-free and overall survival when treated with the PARP inhibitor olaparib versus an anti-androgen treatment.
A new drug called berzosertib, an inhibitor of the DNA-repair protein ATR, has shown very promising results in a variety of cancers with relevant mutations, and is currently being tested in a trial for mCRPC in combination with chemotherapy.
Prostate Cancer: Surgical Castration Linked To Fewer Adverse Events Than Chemical Castration
Bilateral orchiectomy is as effective as treatment with gonadotropin-releasing hormone agonists in controlling prostate cancer and is associated with fewer clinically relevant adverse events, a population-based study has found.1
Androgen-deprivation therapy with surgical or pharmacological castration has long been a mainstay of treatment for metastatic prostate cancer.2 However, due to concerns about cosmetic and psychological effects of surgical castration, that practice has been nearly eliminated in favor of medical castration.
Given that these are 2 accepted alternative means to achieve testosterone blockade, it is important to understand the differences in side effects to properly counsel patients about their choices, said Quoc-Dien Trinh, MD, of Brigham and Womens Hospital and Dana-Farber Cancer Institute in Boston, MA, in an interview with Cancer Therapy Advisor.
A total of 3295 men with metastatic prostate cancer 66 years or older were selected using the Surveillance, Epidemiology and End Results database between January 1995 and December 2009. The men either were treated with GnRHa or underwent bilateral orchiectomy .
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Men who underwent surgical castration had significantly lower risks of experiencing any fractures, peripheral arterial disease, and cardiac-related complications than those who were treated with GnRHa.
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Androgen Receptor Splice Variants
ARVs are truncated versions of the wild type AR that are constitutively active. The truncated portion is typically the C-terminal ligand-binding domain , though at least one variant, ARV8, was reported to have loss of the DNA binding domain . The loss of the LBD makes these variants ligand-independent. The true functional implication of ARVs is not yet completely understood, as direct measurement of the variants has been limited by lack of variant-specific antibodies, requiring proxy assessment using transcribed RNA levels. However, transcribed RNA levels may not be reflective of protein levels, suggesting some degree of post-translational modification .
The role of ARVs in clinical CRPC is being established however. While some CRPC cell lines demonstrate low levels of ARVs, CWR22Rv1 in particular demonstrates almost equal levels of ARV and full-length AR . Hornberg et al. demonstrated that there were higher levels of ARV expression in CRPC bone metastases compared to hormone-sensitive prostate cancer bone metastases, and that ARV expression was associated with poorer prognosis.
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Hormone Therapy For Prostate Cancer
Jump to a section
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 androgens are 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.
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Intratumoral Steroid Hormone Synthesis
PC employs intracrine androgen biosynthesis as another method to allow growth in androgen depleted conditions. Hormonal therapy which lowers circulating testosterone and thus depletes intraprostatic/intratumoral DHT has been the mainstay treatment of advanced PC for many years.52 PC cells contain all the necessary components for androgen biosynthesis, with levels of many key enzymes being increased in recurrent PC.53 The source of androgens in prostatic tissue after ADT involves intracrine production within the gland, converting adrenal androgens to DHT. It was found that DHT measurements in prostatic samples after androgen deprivation therapy remained at 25% the amount measured before anti-hormone treatment.54 Montgomery et al found that this intracrine steroidogenesis occurs not only in primary PC tumors, but also in distant metastases.55 Moreover, CRPC metastatic sites are marked by an augmented expression of steroidogenic genes such as CYP17A1-19A1, HSD3B1-17B3, etc.55 The alternate 5-dione pathway is the major route for DHT synthesis in CRPC. This pathway catalyzes the conversion of dehydroepiandrosterone and androstenedione to DHT while bypassing testosterone completely.52 Enzalutamide is an AR antagonist. Enzalutamide resistant cell lines were found to have increased expression of genes involved in androgen biosynthesis.56
Surgery In Metastatic Disease
Physicians have suggested that the benefits seen from radiation to the prostate point to the benefits of local therapy, raising the question of whether radical prostatectomy might have the same results. Trials are ongoing, and at present the use of surgery should be considered investigational and conducted only within the context of a trial. However, transurethral resection is sometimes needed in men who develop obstruction secondary to local tumor growth. Bilateral orchiectomy can be used to produce androgen deprivation in patients with widely advanced and metastatic prostate cancer.
Since the introduction of LHRH agonist and antagonist therapies, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression, because it avoids the potential flare response that can occur during the first 3 weeks of treatment with an LHRH agonist.
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Cancer That Is Thought To Still Be In Or Around The Prostate
If the cancer is still thought to be just in the area of the prostate, a second attempt to cure it might be possible.
After surgery: If youve had a radical prostatectomy, radiation therapy might be an option, sometimes along with hormone therapy.
After radiation therapy: If your first treatment was radiation, treatment options might include cryotherapy or radical prostatectomy, but when these treatments are done after radiation, they carry a higher risk for side effects such as incontinence. Having radiation therapy again is usually not an option because of the increased potential for serious side effects, although in some cases brachytherapy may be an option as a second treatment after external radiation.
Sometimes it might not be clear exactly where the remaining cancer is in the body. If the only sign of cancer recurrence is a rising PSA level , another option for some men might be active surveillance instead of active treatment. Prostate cancer often grows slowly, so even if it does come back, it might not cause problems for many years, at which time further treatment could then be considered.
Factors such as how quickly the PSA is going up and the original Gleason score of the cancer can help predict how soon the cancer might show up in distant parts of the body and cause problems. If the PSA is going up very quickly, some doctors might recommend that you start treatment even before the cancer can be seen on tests or causes symptoms.
Intermittent Versus Continuous Hormone Therapy
Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.
In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.
At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.
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Adverse Effects Of Androgen Suppression
Surgical and medical castration lead to a number of adverse effects, including the following, that can have a significant impact on a mans quality of life:
- Psychological changes
- Weight gain
In addition, in men with prostate cancer receiving ADT, lean body mass decreases significantly after 12-36 months of treatment.
Uncertainty remains about the impact of androgen ablation on cardiovascular morbidity and mortality. However, the combination of weight gain and anemia in men with asymptomatic cardiovascular disease could adversely affect survival in some cases.
The FDA has advised that manufacturers of gonadotropin-releasing hormone agonists, which are approved for palliative treatment of advanced prostate cancer, must add safety warnings about the increased risk of diabetes and certain cardiovascular diseases in men receiving these medications. The FDA notes that although the risk for these complications appears to be low, physicians should evaluate patients for risk factors for these diseases before prescribing these agents.
Patients receiving GnRH agonists should be actively monitored for diabetes and cardiovascular disease and treated when possible. Periodic measurement of fasting glucose, cholesterol, triglycerides, and blood counts should be performed. In addition, the package inserts for all LHRH medications recommend periodically measuring serum testosterone, because levels above 50 ng/dL do occur and may adversely affect long-term survival.
Acute kidney injury
The Role Of Ar Signaling In Crpc
The expression of PSA is mediated by androgen response elements. This suggests that the increasing PSA during ADT reflects activation of AR transcriptional activity. Consistent with this hypothesis, various recent findings have supported the notion that one of the most important mechanisms in CRPC development is the continuous activation of AR in prostate cancer cells. Several cellular and molecular alterations are related to this post-castration activation of the AR, including incomplete blockade of AR-ligand signaling, AR amplifications, AR mutations, aberrant AR co-regulator activities and AR splice-variant expression.
Enzalutamide is a novel AR antagonist that overcomes resistance to conventional anti-androgens by inhibiting nuclear localization and chromatin binding of AR. According to a recent phase I/II study in patients with mCRPC, the use of enzalutamide is safe, elicits PSA and radiographic response, and results in a median time to progression of 47 weeks. The superiority of enzalutamide over placebo was confirmed in a phase III clinical trial that showed increased overall survival and improvement in all secondary end points in patients with mCRPC after chemotherapy. Despite these encouraging results, after a period of remission that is characterized by significant variation in therapeutic response, these tumors eventually progress.
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Management Of Advanced And Metastatic Disease
AUA/ASTRO/SUO guidelines on advanced prostate cancer separate management considerations into the following four disease states, which encompass the entire continuum of advanced prostate cancer :
These disease states are defined by the following:
- Primary tumor status
- Presence or absence of distant disease on imaging
- Testosterone levels
- Prior chemotherapy exposure
Followup By Primary Care Physicians
The American Cancer Society has released evidence- and expert-based guidelines for the management of prostate cancer survivors by primary care physicians , a response to the fact that as the number of men surviving prostate cancer has increased, reliance on PCPs for their care has grown as well. The guidelines address promotion of healthy lifestyles, surveillance for disease recurrence, screening for second primary cancers, and evaluation and management of adverse physical and psychosocial effects caused by the disease and its treatment. Recommendations include the following :
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Radiation Therapy Versus Surgery
In 2014, the Agency for Healthcare Research and Quality found insufficient evidence to determine whether any type of radiation therapy results in fewer deaths or cancer recurrences than radical prostatectomy does in patients with clinically localized prostate cancer. The importance of dose escalation in disease control complicates the extraction of meaningful conclusions from current radiation therapy treatments .
Brachytherapy has also been compared with surgery in the management of early-stage disease. Direct comparisons are not readily available, but preliminary data from most centers suggest that permanent prostate implants yield comparable local control and biochemical disease-free rates.
Valid comparisons of surgery and radiation therapy are impossible without data from randomized studies that track long-term survival rather than PSA recurrence. Variation in radiation techniques and dosage administered the variable use of androgen ablation, which improves survival in intermediate- and high-risk disease and the variable impact on the quality of life complicate comparison using uncontrolled studies.
How Does Cancer Become Resistant To Hormone Therapy
Cancer progression is much more than growing the tumor and metastasis. It involves thousands of processes inside the cell. It all starts with a few mutations to the DNA of a previously normal cell. This cell loses its restraint and starts to divide without limit. Thats only the early start of cancer.
New cancer cells born programmed to divide rapidly. This rapid division is also disorganized and fosters new DNA mutations. As the DNA continues to mutate, the cell loses its normal functions and looks different from healthy cells. More and more functions are lost or replaced by others, and cancer becomes more aggressive.
Androgen activation and response to testosterone could be one of the functions affected by new DNA mutations. Thus, the resulting cancer cell does not depend on androgens to keep growing. Reducing levels of testosterone, in this case, would not trigger a significant change in growth speed. In other cases, lower testosterone levels are met by an increase of androgen receptors in cancer cells.
Either way, androgen deprivation stops working after a while, and in some cases, it may not work from day one. This is what we call castrate-resistant cancer .
The exact genes and metabolism changes that turn cells into castrate-resistant cancer are still elusive. However, recent studies have shown specific changes in metabolism and genetics.
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New Treatments For Mcrpc
mCRPC remains a clinically challenging late-stage cancer with no curative treatment options. However, the newer hormonal drugs enzalutamide and abiraterone provide a tighter inhibition of androgen signaling, and are often used as first-line treatment in mCRPC. Docetaxel is used in patients for whom treatment with enzalutamide or abiraterone has failed, but it can also be a first-line treatment for mCRPCthis is a decision usually made by oncologists that takes into account patient-specific considerations. Bone metastases, very prevalent in prostate cancer, are treated with Radium-223 or radiation to reduce pain.
In recent years, what has changed in treatment of mCRPC is that clinical guidelines now include mutational testing and analysis of markers to predict the potential effectiveness of newer treatments that involve the immune system.
Quality Of Life With Mcrpc
According to a review published in the British Medical Journal in October 2016, you may not experience pain or other symptoms at this stage of cancer, or you may experience many. Its different for everyone. So along with treating the cancer itself, be sure to talk to your doctors about any symptoms and side effects youre experiencing in order so that the right ways to alleviate them can be found. You should also ask your care team about options for palliative care.
Because it can be very stressful to have advanced prostate cancer, and tough to talk about what it all means for your future, the ASCO urges men to have an open and honest conversation with their care team. Discuss what youre worried about, and whats important to you. There are many ways to look for and get emotional support.
Additional reporting by Andrea Peirce
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