Posts Tagged ‘Keytruda’

Treatment Options For Castrate-Resistant Prostate Cancer

November 2, 2019

Andrew Siegel MD  11/2/19

There are a variety of new treatments for castrate-resistant prostate cancer (CRPC). Today’s entry reviews these options: advanced hormonal therapy, bone-targeted therapy, immunotherapy and cytotoxic therapy.

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Advanced hormonal therapy meds: 5-7 letters, 3-4 syllables, in Scrabble would be of great value!

ADVANCED HORMONAL THERAPY

Abiraterone (Zytiga), approved by the FDA in 2011, works by inhibiting an enzyme in the adrenal steroid biosynthesis pathway, which blocks the production of testosterone and other testosterone-like hormones.  Recall that one of the mechanisms of resistance to androgen deprivation therapy (ADT) is the ability of the prostate cancer cells to produce their own testosterone; Zytiga can prevent this from occurring.  It must be used in conjunction with steroids to counteract side effects including high blood pressure, electrolyte abnormalities and fatigue.

A recently published clinical trial demonstrated that the addition of Zytiga and prednisone to ADT significantly increased overall survival and decreased the risk of prostate cancer progression in men with newly diagnosed metastatic castrate-sensitive prostate cancer, leading to a new FDA approval in 2018.

Enzalutamide (Xtandi), FDA approved in 2012, is a second-generation anti-androgen that works by blocking the activation of the androgen receptor by testosterone. In order for testosterone to function, it must first bind to the androgen receptor to activate it, after which it gets transported into the nucleus of the cell.  Xtandi offers an advantage over the first-generation anti-androgens in that it binds with a stronger affinity to the androgen receptor. It was originally approved only for metastatic CRPC, but because studies showed that it delayed metastases and offered a survival benefit to men with non-metastatic CRPC, it was FDA approved in July 2018 for use in men with non-metastatic CRPC. Potential side effects include fatigue, back pain, diarrhea, constipation, joint aches, cardiac adverse effects, high blood pressure, increased liver enzymes and, rarely, seizures.

Apalutamide (Erleada) in 2018 became the first FDA approved treatment for non-metastatic CRPC.  Erleada works by blocking the activation of the androgen receptor by testosterone, with similar properties to enzalutamide, bicalutamide, and nilutamide.  Clinical studies have demonstrated its ability to significantly delay the time to symptomatic progression, metastasis and death. Side effects include rash, hypothyroidism, fractures, and rare seizures.

Darolutamide (Nubeqa) was FDA approved in July 2019 for the treatment of patients with non-metastatic CRPC. Darolutamide is an androgen receptor inhibitor that inhibits the binding of testosterone to the androgen receptor.  Clinical studies have demonstrated its ability to significantly delay the time to symptomatic progression, metastasis and death. Side effects include fatigue, extremity pain, rash, lower white blood cell count and elevated liver function tests.  Because darolutamide does not cross the blood-brain barrier, central nervous system side effects such as seizures, dizziness and cognitive changes are very rare.

BONE TARGETED THERAPY

Bone metastases are the first site of metastases in the majority of patients with prostate cancer. Prostate cancer cells taking residence in bones can disrupt bone health and cause pain, pathological fractures and compression of nerves and the spinal cord in the circumstance of vertebral metastases.  The combination of an aging male, prostate cancer bone metastases and the use of androgen deprivation therapy (which further accelerates bone loss) creates the perfect storm for the aforementioned bone maladies, referred to asskeletal related events” (SRE).  SRE include pathological fractures, spinal cord compression, and bone pain or impending fracture requiring the necessity for radiation therapy or surgery.

Fact: The condition of prostate cancer that has spread to the bones is referred to as “metastatic prostate cancer” as distinguished from “primary bone cancer.” 

Fortunately, medications are available that help fortify bones that have been weakened either by the accelerated bone loss from androgen deprivation therapy or from the presence of the cancer cells within the bones.  Bone “anti-resorptive therapy” helps strengthen bones by driving calcium into the bones, decreasing the risk of SRE by reducing the amount of bone broken down by the body.

Zoledronic acid (Zometa) is a bisphosphonate given as a 15-minute infusion that is used to prevent SRE and to alleviate bone pain from metastatic CRPC.  It is now infrequently used because clinical trials have demonstrated that Xgeva is better than Zometa in delaying or preventing SRE and does not impair kidney function as Zometa can.

Denosumab (Prolia) is used for patients on ADT (who have not yet developed bone metastases) to help maintain bone health and limit bone loss, used as 60 mg injection every six months.

Denosumab (Xgeva) is used for patients with a rising PSA despite ADT and for patients with bone metastases, used as 120 mg injection every four weeks.

A dental exam is recommended before initiation of the aforementioned bone-targeted therapies because of the potential side effect of osteonecrosis (death of bone tissue from lack of blood supply) of the jaw, a rare complication.  Routine dental checkups every 6 months are advised.

Xofigo (Radium 223 Dichloride) is a radiopharmaceutical drug approved by the FDA in 2013 to treat CRPC metastatic to the bones.  One injection is given intravenously every 4 weeks for a total of 6 doses. It is prescribed for patients with minimally symptomatic or symptomatic bone metastatic CRPC requiring analgesic medication, who have no lymph node enlargement greater than 3 cm in diameter and have no spread of the prostate cancer to organs including the lungs, liver, etc.

Xofigo mimics calcium and forms complexes at areas of increased bone turnover. It contains the radioactive material radium 223, which works at the site of bone metastases, emitting radiation that has an anti-cancer effect by inducing breaks in tumor cell DNA and causing cell death.  It can be absorbed by other organs, particularly those that are very active, including bone marrow (where blood cells are produced) and the digestive system, which can result in side effects in those tissues.  Anemia, low white blood cell counts, low platelet counts as well as bone pain, nausea, vomiting, diarrhea and swelling of the arms and legs may occur. Despite potential side effects, Xofigo has been a valuable addition to the CRPC treatment resources because it delays the time to symptomatic bone metastases and symptomatic SRE, reduces bone cancer pain, and provides a survival benefit.  Furthermore, it has less bone marrow toxicity compared to the previous generation radio-pharmaceuticals.

IMMUNOTHERAPY

The immune system is the body’s natural defense against infection and cancer. In patients with advancing prostate cancer, the immune system is often neutralized by the cancer cells. However, there are means of tapping into one’s immune system to promote the recognition and destruction of cancer cells.

Sipuleucel-T (Provenge) is not on the list of “high-value Scrabble words,” but is an important addition to the prostate cancer weaponry, approved by the FDA in 2010 for patients with progressive metastatic CRPC who are asymptomatic or minimally symptomatic. Provenge is a vaccine that fights prostate cancer by programming one’s immune system to seek out and destroy prostate cancer cells.  Although it can prolong life, it only rarely decreases PSA or reduces metastases.

Immune cells are filtered out from one’s blood and exposed in the lab to cancer antigens and other chemicals that turn the immune cells into a vaccine.  This vaccine is injected back into the body, where it causes an immune response to the cancer cells.

Side effects are flu-like symptoms (fever, chills, muscle aches) that generally are self-limited.

Pembrolizumab (Keytruda) is a type of immunotherapy known as an immune checkpoint inhibitor. It was approved by the FDA in 2017 for use in patients whose prostate cancer demonstrates specific genetic mutations. It works by blocking immune-suppressive signals and activating tumor-killing cells. It is typically used only as a last resort after other treatments have been deemed ineffective. It is given intravenously once every three weeks. Although not all men have a favorable response to this drug, it can be highly effective in those who do respond, with marked reduction in PSA, tumor size, symptoms and progression.

CYTOTOXIC THERAPY   (“cyto” = cells, “toxic” = poisonous)

Medical oncology is the specialty devoted to the use of cancer-killing medications, a.k.a. chemotherapy, to stop malignant cells from dividing, growing and spreading.  Since chemotherapy is most effective for rapidly dividing cells and because many prostate cancers grow relatively slowly, chemotherapy is not usually a primary form of treatment as are surgery or radiation. All rapidly dividing cells are affected by chemotherapy—hair, skin, gastro-intestinal tract, testes, bone marrow. Although side effects can outweigh benefits in the treatment of early prostate cancer, chemotherapy can be beneficial to treat pain and extend life in advanced prostate cancer.

When prostate cancer grows resistant to ADT, chemotherapy becomes a consideration. Chemotherapy is a systemic (as opposed to local) treatment that can control progressive growth and destroy prostate cancer cells that have become resistant to ADT. Although chemotherapy is usually used as a salvage treatment for CRPC or for metastatic prostate cancer, two recent clinical trials have demonstrated an improvement in overall survival using ADT plus chemotherapy (taxotere) in castrate-sensitive prostate cancer, prior to the development of resistance to hormonal therapy.

Taxotere (Docetaxel) was FDA approved in 2004 and when combined with prednisone has been the standard first-line chemotherapy for metastatic CRPC for many years.  It can sometimes have a role in men with high volume prostate cancer that has not been managed with ADT.  It alleviates pain, increases quality of life and increases survival.  Side effects may include suppressed production of blood cells and platelets, fatigue, edema (swelling), neurological toxicity and changes in liver function.  Historically, the standard treatment prior to the Docetaxel era was mitoxantrone (Novantrone) combined with prednisone.

Cabazitaxel (Jevtana) is the newest addition to the chemotherapy weaponry.  FDA approved in 2010, it is useful in prostate cancers resistant to other agents. Its primary toxicity is bone marrow suppression and for this reason it is almost always used in conjunction with a medication to boost infection-fighting white blood cells.

CRPC Management Challenges

Because of the recent availability of many new forms of treatment for CRPC, questions and controversies have arisen regarding benefits, risks and effects on quality of life, costs, use of single versus combined agents, optimal timing (when to use) and sequencing (in what order to use) and how to best measure clinical benefits.  For example, in patients with metastatic CRPC, treatment options include Zytiga, Xtandi, Erleada, Nubeqa, Docetaxel, and Xofigo. Management of CRPC continues to evolve and collaboration among urologist, radiation oncologist and medical oncologist will best determine optimal management.

Wishing you the best of health,

2014-04-23 20:16:29

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Dr. Andrew Siegel is a physician and urological surgeon who is board-certified in urology as well as in female pelvic medicine and reconstructive surgery.  He is an Assistant Clinical Professor of Surgery at the Rutgers-New Jersey Medical School and is a Castle Connolly Top Doctor New York Metro Area, Inside Jersey Top Doctor and Inside Jersey Top Doctor for Women’s Health. His mission is to “bridge the gap” between the public and the medical community. He is a urologist at New Jersey Urology, the largest urology practice in the United States.

The content of this entry is excerpted from his new book, PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families

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Video trailer for Prostate Cancer 20/20

Preview of Prostate Cancer 20/20

Andrew Siegel MD Amazon author page

Prostate Cancer 20/20 on Apple iBooks

PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families is now on sale at Audible, iTunes and Amazon as an audiobook read by the author (just over 6 hours). 

Dr. Siegel’s other books:

FINDING YOUR OWN FOUNTAIN OF YOUTH: The Essential Guide to Maximizing Health, Wellness, Fitness and Longevity

PROMISCUOUS EATING— Understanding and Ending Our Self-Destructive Relationship with Food

MALE PELVIC FITNESS: Optimizing Sexual and Urinary Health

THE KEGEL FIX: Recharging Female Pelvic, Sexual, and Urinary Health