Overview

When prostate cancer has been detected or has returned following initial treatment with surgery, radiation therapy and/or hormone therapy, it is said to be recurrent or relapsed.  The following is a general overview of the treatment of recurrent prostate cancer. Recent advances in treatment have resulted in new treatment options that reduce symptoms and improve survival. Each person with prostate cancer is different, and the specific characteristics of your condition will determine how it is managed. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

Treatment of recurrent prostate cancer depends on what treatment a patient has previously received and the extent of the cancer. Some patients have only a rise in PSA level as evidence of recurrent cancer. Other patients will have evidence of recurrent cancer on x-rays or scans. Patients who have prostate cancer that continues to grow despite hormone therapy are referred to as having hormone-refractory prostate cancer (HRPC).

Recurrent Prostate Cancer After Surgery

When prostate cancer shows signs of returning after primary treatment with prostatectomy, decisions about additional treatment depend in part on whether or not the cancer has metastasized (spread) to other parts of the body. Cancer that is appears confined to the area of the prostate may be treated with radiation therapy with or without androgen-deprivation therapy (ADT).

If the cancer is thought to have spread to other locations in the body systemic treatment with ADT is the primary approach and may be used with or without radiation therapy. ADT slows or stops cancer growth by reducing levels of male hormones such as testosterone. Recurrent prostate cancer usually can be controlled with ADT for a period of time, often several years. Eventually, however, most prostate cancers continue growing despite the hormone therapy. Chemotherapy is also being increasingly used in men with prostate cancer that has recurred in areas distant from the prostate because it has been demonstrated to improve survival.1

Recurrent Prostate Cancer After Radiation Therapy

Once a patient has received radiation therapy to the prostate gland, more radiation therapy typically cannot be given to the same area safely. Systemic treatment with ADT is the mainstay of treatments for individuals with recurrent prostate cancer following primary treatment with radiation. Rarely, surgeons have removed the prostate gland for persistent cancer after radiation therapy. Other surgeons have used cryosurgery, which is a local treatment where the prostate gland is frozen with a probe. Complications of surgery or cryosurgery, however, tend to be more frequent in patients previously treated with radiation therapy. If a patient is not a candidate for these types of local therapies or ADT other systemic treatments like chemotherapy or immunotherapy are used.

Hormone-Refractory Prostate Cancer (HRPC)

For patients treated with ADT, the treatment may control the growth of the cancer for several years. Eventually, however, most prostate cancers stop responding to this treatment and begin to grow again. Cancers that grow in spite of ADT are called hormone-refractory. Treatment options for HRPC include chemotherapy, immunotherapy, additional hormonal therapy, local radiation therapy for the purpose of alleviating symptoms, or participation in clinical studies evaluating new treatments.

Chemotherapy

Chemotherapy is a systemic therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer.  Several chemotherapeutic drugs have demonstrated the ability to kill prostate cancer cells in patients with recurrent prostate cancer. In particular, the chemotherapy drugs mitoxantrone (Novantrone®), docetaxel (Taxotere®), paclitaxel and estramustine have all been demonstrated to have some effectiveness in treating prostate cancer.2, 3

Docetaxel chemotherapy was demonstrated to improve survival of men with advanced HRPC in 2004 and has remained the mainstay of chemotherapy often utilized in combination with prednisone or estramustine.  More recently, several new chemotherapy and targeted therapy drugs have been approved for the treatment of advanced prostate cancer. A Targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes.  Doctors are working to determine the best sequence, combinations, and timing of utilization.

Cabazitaxel (Jevtana®): Cabazitaxel is administered intravenously and has been demonstrated to improve time to cancer progression and overall survival in men with HRPC previously treated with docetaxel.   Cabazitaxel’s primary side effect is neutropenia, and it is recommended that patients receive a white blood cell growth factor if they are at high risk of this complication.4

Sipuleucel-T( Provenge®): Sipuleucel-T is actually an immunotherapy that prompts the body’s immune system to respond against the cancer. A Phase III clinical trial that contributed to the FDA approval of sipuleucel-T was a study known as IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment) which demonstrated an improvement in overall survival for men treated with sipuleucel-T. The main side effects reported were chills, fever, and headache.5

Hormone Therapy

Newer hormonal medications that inhibit the synthesis of androgen (abiraterone) and block androgen receptor signaling (enzalutamide) are now FDA-approved for the treatment of metastatic prostate cancer after treatment with chemotherapy, and are being evaluated for use earlier in the disease like when the PSA begins to rise or before chemotherapy.6, 7, 8

Abiraterone (Zytiga®) Abiraterone is an oral targeted agent that blocks the production of androgens not only by the testes, but also by the adrenal glands and the tumor itself.  Abiraterone when administered with prednisone has been shown to improve quality of live and delay patient-reported pain progression in HRPC patients.  Although this medication is generally well-tolerated, side effects may include fatigue, high blood pressure, and electrolyte or liver abnormalities and patients need to be monitored regularly.6

Enzalutamide (Xtandi®) Enzalutamide targets multiple steps in the androgen-receptor–signaling pathway, interfering with molecular pathways that help the prostate cancer grow. What’s more, the drug does not cause side effects commonly associated with chemotherapy, such as nausea and hair loss. Enzalutamide has been shown to improve survival, reduce the risk of cancer progression, and delay the need for additional chemotherapy in men with HRPC.7, 9

Immunotherapy

Biological therapy is referred to by many terms, including immunologic therapy, immunotherapy, or biotherapy. Biological therapy is a type of treatment that uses the body’s immune system to facilitate the killing of cancer cells. Types of biological therapy include interferon, interleukin, monoclonal antibodies, colony stimulating factors (cytokines), and vaccines.  Biologic therapies are being developed for the treatment of prostate cancer.  Sipuleucel-T( Provenge®)  is an immunotherapy that prompts the body’s immune system to respond against the cancer, and was the first to be approved by the FDA.

Sipuleucel-T is an immunotherapy that prompts the body’s immune system to respond against the cancer. A Phase III clinical trial that contributed to the FDA approval of Sipuleucel-T was a study known as IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment). The results of this study were presented at the 2010 Genitourinary Cancers Symposium, and the final results were published in The New England Journal of Medicine.5

To evaluate the effect of Sipuleucel-T among men with metastatic, androgen-independent prostate cancer, researchers conducted a Phase III clinical trial known as IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment). The trial enrolled 512 men. Study participants were treated with either Sipuleucel-T or a placebo and then directly compared. Median overall survival was 25.8 months among men treated with Provenge compared with 21.7 months among men treated with placebo.

  • Three-year survival was 31.7% among men treated with Sipuleucel-T compared with 23% among men treated with placebo.
  • Sipuleucel-T did not significantly delay cancer progression.
  • Side effects of Sipuleucel-T included chills, fever, and headache. Most of these side effects were low grade and of short duration.

Treatment of Bone Complications

Patients with advanced prostate cancer can have cancer cells that have spread to their bones, called bone metastases.  Bone metastases commonly cause pain, increase the risk of fractures, and can lead to a life-threatening condition characterized by an increased amount of calcium in the blood called hypercalcemia. Treatments for bone complications may include drug therapy or radiation therapy.

Zoledronic acid (Zometa®): Zoledronic acid is a bisphosphonate drug that can effectively prevent loss of bone that occurs from cancer that has spread to the bones thereby reducing the risk of fractures, and decreasing pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Zoledronic acid may be used to reduce the risk of complications from bone metastases or to treat cancer-related hypercalcemia.10

Denosumab (Xgeva™): Denosumab targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Studies have suggested that Denosumab may be more effective than Zoledronic acid at delaying bone complications in prostate cancer patients with bone metastases.  Denosumab is associated with side effects including hypocalcemia (low levels of calcium in the blood) and osteonecrosis of the jaw (death of bone in the jaw).10, 11

Xofigo® (radium Ra 223 dichloride): Radium 223 is a targeted radiopharmaceutical agent that binds with minerals in the bone to deliver radiation directly to bone tumors, thereby limiting the damage to the surrounding normal tissues. The U.S. Food and Drug Administration (FDA) approved the drug in May 2013 after a trial known as Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) was stopped early after an interim analysis showed that treatment with significantly improved survival.12

Radiation therapy: Pain from bone metastases may also be relieved with radiation therapy directed to the affected bones.

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of prostate cancer will result from continued participation in appropriate clinical trials. Developing and exploring immunotherapy and single or multi-agent chemotherapy agents as a treatment approach for patients with advanced prostate cancer is the main area of active investigation.

Custirsen: Custirsen inhibits the production of clusterin, a protein associated with treatment resistance in a number of cancers, including prostate cancer. Adding agents with novel or different mechanisms of action to a docetaxel-backbone remains an area of significant interest. Results are pending from the phase III trials combining docetaxel + prednisone with custirsen,

Orteronel: Orteronel is a CYP17A inhibitor but is more specifically a 17,20-lyase inhibitor. It is currently being tested in a phase III trial comparing orteronel and prednisone to placebo and prednisone.

Tasquinomod: Tasquinomod is an orally active drug that has anti-angiogenic (prevents blood vessel growth n the cancer) activity and other anti-cancer properties.  It is currently in ongoing phase III clinical trials.

Novel Immunotherapies: Novel vaccine strategies to harness the immune system are being tested, such as PROSTVAC in asymptomatic, chemotherapy-naïve men prostate cancer Other immune based strategies include inhibition of immune check points using Ipilimumab, which is a monoclonal anti-CTLA4 antibody that binds to a receptor on T cells, blocking CTLA4 and, in turn, activating T-cell anti-tumor activity.

References

1 Sweeney C., et al. Impact on overall survival with chemohormonal therapy versus hormonal therapy for home-sensitivity newly metastatic prostate cancer: An ECOG-led phase III randomized trial. ASCO 2014; Abstract LBA2.

2 Tannock I, de Wit R, Berry W, et al.Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004; 351:1502-1512.

3 Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New England Journal of Medicine. 2004; 351:1513-1520.

4 de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet 2010; 376: 1147.

5 Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411.

6 Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. The Lancet Oncology. 2013; 14(12):1193-1199.

7 Beer TM, Armstrong AJ, Sternberg CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Presented at the 2014 Genitourinary Cancers Symposium. Journal of Clinical Oncology. 2014; 32 (supplement 4; abstract LBA1).

8 Nelson J, Banato A, Battistini B, Nisen P.  The endothelin axis: emerging role in cancer. Nat Rev Cancer2003;3(2):110-116.

9 Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Eng J Med 2012; 367: 1187.

10 Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. The Lancet. 2011;377:813-22.

11 Smith MR, Saad F, Coleman R et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. Early online publication November 16, 2011.

12 Michalski J, Sartor O, Parker C, et al. Radium-223 dichloride (Ra-223) impact on skeletal-related events, external-beam radiotherapy (EBRT), and pain in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Updated results from the phase III ALSYMPCA trial. Proceedings of the 55th Annual Meeting of the American Society of Radiation Oncology. International Journal of Radiation Oncology Biology Physics. 2013; 87(2): S108-S109. Abstract 265.

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