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What Does Castrate Resistant Prostate Cancer Mean

Followup By Primary Care Physicians

Treating Non-Metastatic Castrate Resistant Prostate Cancer | Ask a Prostate Expert, Mark Scholz, MD

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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Other New Approaches In Mcrpc

Other drugs in clinical trials for mCRPC do not rely on the presence of defined mutations. Here, I discuss only those that already have promising preliminary results:

Most prostate cancer cells express a protein called PSMA on their surface. In fact, PSMA is almost exclusively found on prostate cancer cells, making it a good therapeutic target. The novel drug 177Lu-PSMA-617 is a radioactive molecule attached to another molecule that specifically targets cells expressing PSMA. The most recent results from a randomized clinical trial where men received either LuPSMA or the chemotherapy drug cabazitaxel show that response rate was higher with LuPSMA than with cabazitaxel.

Currently, there are two other radionuclide conjugates that target PSMA in trials: BAY 2315497 and 225AcJ591.

PSMA can also be targeted by other means, one of which is a very interesting approach known as CAR T-cell treatment, currently available in two trials. CAR T-cell treatment is beneficial in liquid tumors of the blood or bone marrow, but has yet to be validated in solid tumors like prostate cancer. However, some results are promising. The presence of a good target for these engineered cancer-killing immune cells is a good omen in prostate cancer, because identifying specific targets in solid tumors is a major hurdle in designing CAR T-cell treatments.

If Treatment Does Not Work

Recovery from cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.

This diagnosis is stressful, and for some people, advanced cancer may be difficult to discuss. However, it is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, and knowledge to support patients and their families and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.

People who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment, including a hospital bed, can make staying at home a workable option for many families. Learn more about advanced cancer care planning.

After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss.

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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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Auy922 Decreases Ar Transcriptional Activity In Myc

Therapeutic effects of human monoclonal PSMA antibody

To assess the activity of AUY922 on the attenuation of transcriptional activity in vivo, we used immunostaining to determine the expression of the c-MYC transgene, which in this tumor model is driven by AR transcription via a probasin promoter , . Docetaxel treatment did not induce a loss of c-MYC expression compared to vehicle treated tumors , which was consistent with AR expression in tumor tissues. In contrast, tumors treated with AUY922, displayed significant reduction of c-MYC expression compared to vehicle treatment and docetaxel treatment . Further, combination treatment exhibited similar loss of c-MYC expression compared with AUY922 single treatment, and was significant when compared to docetaxel single treatment .

AUY922 and docetaxel combination therapy significantly attenuate AR transcriptional activity and increase tumor cell death in vivo.

Representative c-MYC immunostaining. Positive nuclear staining for c-MYC was quantified using aperio imagescope analysis of 6 random fields at x40 magnification. Scale bar=500 µM. Two-tailed t-test: **** p< 0.0001 AUY922 versus vehicle ** p=0.006 AUY922 versus docetaxel * p=0.03 combination versus docetaxel. Representative cleaved caspase-3 immunostaining. Positive nuclear staining for cleaved caspase-3 was quantified using aperio imagescope analysis of 6 random fields at x20 magnification. Scale bar=500 µM. Two-tailed t-test: **** p< 0.0001 combination versus single treatments.

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Coactivators Or Corepressor Modification

Ligand independent activation of AR signaling can also be achieved by interactions with other cytokines, growth factors and hormones. In an androgen-depleted state, IL-6 can potentiate the existing androgens as well as self-activate AR at about half of its functional capacity.48,49 Insulin like growth factor-1 , epidermal growth factor and keratinocyte growth factor have also been found to directly activate the AR in the absence of androgens50 with use of bicalutamide completely inhibiting activation of AR by these factors.50 In addition, elevated IGF binding protein corresponds to faster progression to CRPC and lower survival in men with metastatic PC.51

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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Treatment By Stage Of Prostate Cancer

Different treatments may be recommended for each stage of prostate cancer. Your doctor will work with you to develop a specific treatment plan based on the cancers stage and other factors. Detailed descriptions of each type of treatment are provided earlier on this same page. Clinical trials may also be a treatment option for each stage.

Early-stage prostate cancer

Early-stage prostate cancer usually grows very slowly and may take years to cause any symptoms or other health problems, if it ever does at all. As a result, active surveillance or watchful waiting may be recommended. Radiation therapy or surgery may also be suggested, as well as treatment in clinical trials. For those with a higher Gleason score, the cancer may be faster growing, so radical prostatectomy and radiation therapy are often recommended. Your doctor will consider your age and general health before recommending a treatment plan.

ASCO, the American Urological Association, American Society of Radiation Oncology, and the Society of Urologic Oncology recommend that patients with high-risk early-stage prostate cancer that has not spread to other areas of the body should receive radical prostatectomy or radiation therapy with hormonal therapy as standard treatment options.

Locally advanced prostate cancer

Watchful waiting may be considered for older adults who are not expected to live for a long time and whose cancer is not causing symptoms or for those who have another, more serious illness.

Remission And The Chance Of Recurrence

About Metastatic Castrate-Resistant Prostate Cancer

A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having no evidence of disease or NED.

A remission can be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. Although there are treatments to help prevent a recurrence, such as hormonal therapy and radiation therapy, it is important to talk with your doctor about the possibility of the cancer returning. There are tools your doctor can use, called nomograms, to estimate someone’s risk of recurrence. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.

In general, following surgery or radiation therapy, the PSA level in the blood usually drops. If the PSA level starts to rise again, it may be a sign that the cancer has come back. If the cancer returns after the original treatment, it is called recurrent cancer.

When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence, including where the recurrence is located. The cancer may come back in the prostate , in the tissues or lymph nodes near the prostate , or in another part of the body, such as the bones, lungs, or liver . Sometimes the doctor cannot find a tumor even though the PSA level has increased. This is known as a PSA recurrence or biochemical recurrence.

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Metastatic Hormone Sensitive Prostate Cancer

This form of prostate cancer can be an initial diagnosis but more often refers to cases where surgeries or other initial treatments to remove tumors from the prostate havent succeeded in stopping its progression.

Notably, too, these cases are defined by metastasis, meaning it has started to spread to other structures in the body, such as bones or the lymph nodes. However, the development of castration resistance is part of the eventual and expected progression of the diseaseeven while on ADT.

Selection Of Therapy For Crpc

With the range of newer treatment options becoming available, it is clear there will be a need to more carefully define the most appropriate treatment for individual patients with CRPC. As the incidence of prostate cancer is disproportionately high in elderly men, consideration should be given to life expectancy issues, functional status, and the ability of a patient to tolerate potential side effects of therapies . Because elderly patients also may benefit from chemotherapies to the same degree that younger patients do, we should ensure that all treatment options that prolong survival, control symptoms, reduce pain, and improve quality of life are available to those patients with good clinical status. Strategies such as proteomic profiling have been used to define markers that predict docetaxel resistance in men with mCRPC, and use of such biomarkers potentially could better define which patients will experience recurrence early on docetaxel therapy and direct these patients to a more appropriate therapy . Other surrogate biomarkers for prediction of clinical benefit in mCRPC include PSA, bone turnover markers, bone pain, bone scans, and circulating tumor cells . The use of these surrogate biomarkers has the potential to improve patient selection strategies, and more rapidly identify agents that merit further testing in phase 3 clinical trials, as well as accelerate phase 3 testing. However, these markers will require validation for use in patients with mCRPC .

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The Role Of A Multidisciplinary Care Team In Treatment

Keep in mind that the optimal treatment strategy for mCRPC is different for each person and that its a complicated disease to treat. Thats why its important to assemble a team of doctors and specialists to keep your treatment and you on track.

Your team should include an experienced urologist, advises Cookson, as well oncologists who are comfortable with the newer treatments and know how to use them.

A study published in July 2015 in the Journal of Urology agrees, finding that with so many new treatments coming on board, doctors have to juggle a lot of factors when figuring out your best next steps from what kind of symptoms you have to your personal preferences, as well as any other health conditions that may have to be taken into account when coming up with a treatment strategy.

Its also important for your care team to review the medicines youve already taken for prostate cancer, and plan the sequence of the medicines youll take next. Getting the order right is important because certain drugs can make subsequent treatments more, or less, effective.

Your care team should also watch you closely to determine whether you have any resistance to any medicines, so that they can make changes quickly if necessary.

Ideally, your care team should possess expertise in distinct domains of cancer care, such as imaging, chemotherapy, radiation, and surgery, according to a study published in the Annals of Oncology in August 2015.

Aberrant Activation /outlaw Pathway

Reactive stroma component COL6A1 is upregulated in castration

While all the prior mechanisms mediate increased AR activity in the presence of ligand, ligand-independent AR activation is also an important mechanism of progression to castration-resistance. Various in vitro studies have suggested that multiple growth factors, cytokines, and kinase pathways increase AR signaling, thereby promoting progression to castration resistance in a ligand-independent manner . Identification and characterization of those ligand-independent pathways can lead to additional targeted therapies.

The PI3K pathway is another important player in this process. The loss of the tumor suppressor PTEN protein, which is a negative inhibitor of the PI3K/AKT pathway, is identified in nearly all metastatic prostate cancers. Its activation has been associated with development of CPRC in various preclinical models . PI3K, specifically the p110β isoform, has been strongly associated with prostate cancer growth and progression, through basal activation of AKT in prostate cancer models. The PI3K/AKT pathway is downstream of key receptor tyrosine kinases such as EGFR, IGFR, c-met, but some studies suggest independent activation of this pathway . While it is also upstream of some critical signaling proteins, such as mTOR, it has also been found that AKT directly phosphorylates AR at two locations, Ser-217 and Ser-791, particularly in a castrate-state, though the clinical significance is not yet certain .

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Active Surveillance And Watchful Waiting

If prostate cancer is in an early stage, is growing slowly, and treating the cancer would cause more problems than the disease itself, a doctor may recommend active surveillance or watchful waiting.

Active surveillance. Prostate cancer treatments may seriously affect a person’s quality of life. These treatments can cause side effects, such as erectile dysfunction, which is when someone is unable to get and maintain an erection, and incontinence, which is when a person cannot control their urine flow or bowel function. In addition, many prostate cancers grow slowly and cause no symptoms or problems. For this reason, many people may consider delaying cancer treatment rather than starting treatment right away. This is called active surveillance. During active surveillance, the cancer is closely monitored for signs that it is worsening. If the cancer is found to be worsening, treatment will begin.

ASCO encourages the following testing schedule for active surveillance:

  • A PSA test every 3 to 6 months

  • A DRE at least once every year

  • Another prostate biopsy within 6 to 12 months, then a biopsy at least every 2 to 5 years

Treatment should begin if the results of the tests done during active surveillance show signs of the cancer becoming more aggressive or spreading, if the cancer causes pain, or if the cancer blocks the urinary tract.

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.

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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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