The Return of My Cancer -Emerging Effective Therapies Jianqing Lin, MD

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1 Februray, 2013 The Return of My Cancer -Emerging Effective Therapies Jianqing Lin, MD

2 Why/How my cancer is back after surgery and/or radiation? Undetected micro-metastatic disease (spreading) before local treatment

3 What are the treatment options now? Informed decision making to improve patient care and survival Individualized care (personalized medicine): goal Disease state dependent

4 70-80% 20-30% Death from co-morbidities Death from disease Prostate cancer clinical-states model Scher et al: J Clin Oncol 26:

5 Early Presentation: Cancer may come back in the prostate or in other parts of the body May need re-biopsy to confirm (local or distant spots) Urinary symptoms (weak flow of urine or frequent urination etc) Bone pain related to disease Most patients: rising PSA without symptoms

6 What is Prostate-Specific Antigen (PSA)? A glycoprotein discovered in 1970s, An enzyme produced by prostate gland, secreted into the male ejaculate, regulated by male hormone (androgen receptor), Abnormal PSA: Benign conditions: BPH, prostatitis, prostate infarct or manipulation etc. not cancer specific Cancer specific if prostate is removed already or radiated Monitoring changes of PSA is recommended after local treatments

7 Natural History of a Rising PSA after surgery ( old data ) Time from RP to a rising PSA Time from BCR to clinical metastases Time from clinical metastases until death 2 years 8 years 5 years Life expectancy after failed surgery 15 years Pound CR, et al. JAMA. 1999; 281:

8 Diagnostic studies and re-staging CAT scan and bone scan to rule out distant metastasis, Positive Negative MRI pelvis to determine local recurrence. If scans are negative, your cancer maybe still local, may still be cured: Additional radiation; or Salvage surgery

9 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy

10 What is hormonal therapy? Treatment that adds, blocks, or removes hormones. For prostate cancer, it is to slow or stop the growth of cancers Drugs may be given to block the body s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, and hormone treatment. Approved for metastatic prostate cancer treatment

11 Hormonal Therapy for Prostate Cancer (traditional) Hormone therapy Advantages disadvantages note Orchiectomy Cost-effective Permanent, disfiguring LHRH agonist reversible expensive leuprolide, goserelin LHRH antogonist reversible expensive Degarelix (Firmagon) Anti-androgen therapy Noncastrating, improved energy, libido, potency Expensive, gynecomastia CAB reversible Expensive, increased side effects flutamide, bicalutamide, nilutamide, 5α reductase inhibitors; ketoconazole No evidence of superior to LHRH alone CAB: Combined androgen blockade, Estrogen therapy (DES, PC-SPES): Not used now

12 Negative Aspects of Androgen Deprivation Hot flashes (Megesterol acetate, anti-depressants, phytoestrogens) Loss libido / erectile dysfunction (sildenafil, vardenafil, tadalafil) Bone mineral loss/ accelerated osteopenia (zolendronic acid, risedronate, alendronate, calcium, vitamin D) Weight gain Changes in lipid/ glycemic metabolic profiles (?insulin sensitizing agents, lipid lowering, high blood pressure meds) Anemia (erythropoeitin) Neuro-cognitive changes

13 Long Term side Effect of Androgen Deprivation Therapy Hyperglycemia Insulin Resistance Metabolic Complications of ADT Metabolic Syndrome Dyslipidemia

14 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy),

15 Provenge Treatment Process

16 PROVENGE (Sipuleucel-T) cellular immunotherapy Approved by FDA on 4/29/10 Consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs), that have been activated during a defined culture period with a recombinant human protein, PAP-GM-CSF, an immune cell activator. Process: 1) standard leukapheresis to obtain PBMC 3 days prior to the infusion date; 2) ex vivo culture with PAP-GM-CSF, the recombinant antigen binding to and being processed by APCs; 3) Infusion back to patient Extend life for 4.1 months (median)

17 Androgen Receptor: remains a key target for treatment New finding: hormone-refractory cancer still needs androgen to grow still androgen sensitive -> term changes castrate resistant; Newly approved drugs: Abiraterone (Zytiga): Oral Inhibits testosterone synthesis/production in testis, adrenal glands and prostate, and cancer cells Enzalutamide (Xtandi): Oral pure antiandrogen/novel androgen receptor blockade More are coming

18 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy), Chemotherapy,

19 Chemotherapy More toxic but generally tolerable Intravenously given Need to be followed more closely Two drugs proved to prolong life: Docetaxel (Texotere) first line Cabazitaxel (Jevtana): second line

20 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy), Chemotherapy, Bone targeted treatment

21 Bone Targeted Therapies Vitamin D and Calcium daily Denosumab (Xgeva) To prevent bone loss, bone damage from cancer such as fractures Every 4 6 weeks Mild side effects but needs to be monitored regularly Bisphoshonates: Zometa Similar to Xgeva Need to monitor kidney function Radiopharmaceuticals (liquid radiation): Alpharadin or samarium RANKL: receptor activator of nuclear factor κ- B ligand

22 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy), Chemotherapy, Bone targeted treatment Palliative therapy ( to lessen bone pain): Pain control, external radiation therapy, internal radiation therapy with radioisotopes),

23 Treatment options for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy), Chemotherapy, Palliative therapy ( to lessen bone pain): Pain control, external radiation therapy, internal radiation therapy with radioisotopes), Clinical trials: Many Most : new anticancer drugs (+/- radiation).

24 Emerging therapies for recurrent prostate cancer Additional radiation therapy (called salvage radiation): after surgery or seeds radiation. Prostatectomy (initially treated with radiation, rarely done). Hormone therapy: Firmagon, Zytiga, Xtandi etc Biologic therapy (ie, Sipuleucel-T) (already treated with hormone therapy), Chemotherapy, Palliative therapy ( to lessen bone pain): Pain control, external radiation therapy, internal radiation therapy with radioisotopes), Clinical trials: Many Most : new anticancer drugs (+/- radiation).

25 Summary A disease of long nature history Relax, don t be panic Survivorship: a multimodality approach, primary care MD s involvement is key Bone is the most common metastatic site -> Bone-targeted therapy reduce risk of fracture Androgen deprivation is main stay of treatment for advance PCa but has side effects Androgen-AR axis remain the main target for the treatment of PCa novel drugs, less toxic Chemotherapy, active immune-therapy improve survival Many drugs are on the way clinical trials are highly encouraged

26 Questions and Discussion

Definition Prostate cancer

Prostate cancer 61 Definition Prostate cancer is a malignant neoplasm that arises from the prostate gland and the most common form of cancer in men. localized prostate cancer is curable by surgery or radiation