Prostate Cancer: What's New in Systemic Therapy?

Educational Objectives

The goal of this program is to improve the management of advanced and hormone refractory prostate cancers. After hearing and assimilating this program, the clinician will be better able to:

1.   Prevent toxicities associated with androgen deprivation therapy (ADT) by providing appropriate monitoring.

2.   Recognize and respond to bone mineral density (BMD) loss in androgen-deprived patients.

3.   Assess prostate tumors for signs of androgen independence and modulate therapy accordingly.

4.   Compare the efficacy of traditional chemotherapy regimens for treating metastatic prostate disease.

5.   Apply recent advances in immunotherapy and angiogenesis-inhibiting therapy to the treatment of prostate can­cer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Oh is on the Speaker’s Bureau for sanofi-aventis, and has received research funding from Genentech and sanofi-aventis. Drs. Ryan and Small and the planning committee reported nothing to disclose. In his lecture, Dr. Oh presents information related to off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Oh, Dr. Ryan, and Dr. Small were recorded at UCSF Annual Advanced Seminar on Innovations in Prostate Cancer, held February 13-14, 2009, in San Francisco, CA, and sponsored by the Department of Urology at the University of California, San Francisco, School of Medicine.  The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

Risks of Androgen Deprivation Therapy (ADT): What Do We Know?

William K. Oh, MD, Associate Professor of Medicine, Harvard Medical School, and Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA

Introduction: ADT affects quality of life more subtly than other cancer events; quality of life issues more significant with prostate cancer due to longer median survival rates; use of ADT has risen across entire spectrum of prostate cancer care

ADT toxicity: affects all systems moderated by testosterone; ADT side effects  —  hot flushes, loss of libido, weight gain, decreased muscle mass, accelerated osteoporosis, bone fractures, decreased cognitive function (typically un­derappreciated; data lacking); ADT responses heterogeneous; some patients experience severe side effects; in oth­ers, side effects minimal; informing patients of possible unusual responses advised; luteinizing hormone-releasing hormone (LHRH) agonists  —LHRH agonists typically decrease BMD; significant BMD decrease observed after 12 mo therapy (2%-3% per year of androgen deprivation); BMD loss creates exponential rise in vertebral fracture risk; Shahinian study  —  found »7% increased risk for vertebral fractures in patients receiving ADT; dose-response relationship present; risk for fractures increased with extended duration of therapy; data in literature show fractures increase mortality rates in older adults, even those without cancer

Bisphosphonates for bone loss: study found administration of pamidronate before start of LHRH agonist therapy prevented loss of BMD; zoledronic (eg, Zometa) acid administered every 3 mo increased BMD at 1 yr; results consistent in patients with preexisting mild osteopenia or osteoporosis; alendronate (Fosamax)  —  oral once-weekly bisphosphonate; results comparable to those with zoledronic acid; useful for physicians who have diffi­culty providing infusions

Adverse effects: include flu-like symptoms (eg, fever, myalgias), nausea, and fatigue; renal toxicity  —  remains con­troversial; zoledronic acid labeling revised to recommend modulating dosages based on renal function; 25% risk for renal insufficiency observed in speaker’s practice; osteonecrosis of the jaw  —  relatively rare; patients receiv­ing bisphosphonates warned against undergoing tooth extractions and referred to dental specialists if procedure needed

Estrogens to regulate BMD: castrated patients typically deprived of both testosterone and estrogen; estrogen consti­tutes critical bone-building hormone; selective estrogen receptor modulators (SERMs; eg, toremifene) activate es­trogen receptor-a in bones, increasing BMD in castrated men; toremifene therapy associated with decreased rates of new vertebral fractures (from 5% to 2.2%) in patients with loss of BMD; all estrogenic compounds associated with increased risk for thromboembolism; frequency of events  low, but risk for thromboembolism increased  dur­ing initial years of therapy; thromboembolism associated with estrogenic compounds typically predicted by spe­cific risk factors (eg, advanced age, recent surgery, history of venous thromboembolism)

Monitoring ADT: assess patients for loss of height; dual energy x-ray absorptiometry (DEXA) to establish baseline BMD recommended; all patients receiving hormones should also receive calcium and vitamin D supplements; ex­ercise known to increase BMD; alcohol and smoking known to decrease BMD; for patients who already have os­teoporosis, bisphosphonate therapy recommended; patients with osteopenia also may receive bisphosphonates; monitor BMD every 1 to 2 yr

Cardiovascular risks: 5 studies suggest cardiovascular side effects associated with ADT; effect modest and depen­dent on preexisting risk of dying from myocardial infarction (MI); cardiovascular risks may result from unneces­sary overuse of ADT; assess cardiovascular risks when determining timing of ADT; without comorbidities, 6 mo of ADT associated with significant increases in survival; with specific comorbidities (eg, cardiovascular risk fac­tors), ADT is associated with decreased longevity

Large population-based Canadian study: rate of fragility fractures significantly increased in ADT group; increase in development of diabetes (associated with weight gain) modest over 10-yr period; ADT increased dyslipidemia rates; difference in rates of MI in ADT and non-ADT groups of borderline statistical significance, sudden cardiac death rates identical; summary  —cardiovascular risks statistically modest, but referral to cardiologist before initi­ating hormone therapy advised

Castration-resistant Prostate Cancer: What Is It?

Charles J. Ryan, MD, Associate Clinical Professor of Medicine, Department of Medicine, University of Cali­fornia, San Francisco, School of Medicine

Introduction: terminal cases of prostate cancer typically exhibit castration resistance; frequently indicated by re­duced testosterone levels, with rising prostate-specific antigen (PSA) levels; hypothesis that castration resistance equates with  development of hormone hypersensitivity

Refractory or hypersensitive? speaker asserts androgen-independent prostate cancer may not exist or may exist at later time in natural history of disease than currently thought; androgen receptor amplification  —  one of most im­portant events in transition that enables cancer to grow in androgen-depleted milieu; testosterone receptors increase dramatically as disease progresses and adapts to hormone deprivation; secondary androgens produced by adrenal gland in androgen-deprived patients; LHRH modulates only testicular androgens; dehydroepiandrosterone (DHEA) and androstenedione  —  androgens that remain measurable and do not necessarily decline during LHRH therapy; Cancer and Leukemia Group B (CALGB) study  —  patients treated with ketoconazole (suppressor of adrenal andro­gen synthesis); 30% of patients in phase III trial responded to ketoconazole, frequently for long term (³2 yr); as dis­ease progressed on ketoconazole therapy, androgen levels increased; so, either ability of ketoconazole to suppress androgen formation decreases, or some other pathway of androgen production begins; patients with higher baseline androgen levels experienced better response to ketoconazole, with associated increases in survival

Autocrine-paracrine disease: hypothesis  —  prostate cancer becomes autocrine-paracrine disease able to create its own steroid hormones and use them for autocrine growth; University of Washington study  —  healthy volunteers subjected to 1 mo of androgen suppression via acyline; serum dihydrotestosterone dropped to nearly undetectable levels, but subsequent prostate biopsies exhibited only minor decreases of intraprostatic testosterone; in healthy set­tings, prostate cells trap hormones beneficial to preserving growth; Roswell Park Cancer Institute studies  —  found intraprostatic testosterone levels may remain average in patients receiving ADT; 5-a reductase converts testoster­one to dihydrotestosterone, consistent with autocrine characteristics; separate study discovered elevated 5-a reduc­tase expression associated with androgen-stimulated benign prostate tumors, androgen-stimulated or untreated prostate carcinomas, and recurrent prostate cancer after transurethral resection; Stanbrough study  —  analyzed gene expression in bone marrow biopsies harvested from patients with castration-resistant prostate cancer; focused on genes responsible for processing steroid hormones into androgens; expression of genes associated with steroid pro­cessing and conversion to androgens increased 2- to 5- fold in patients with androgen-independent tumors; abiraterone  —  investigational drug with improved adrenal androgen suppression; produces significant PSA de­clines; data increasingly indicate that androgen suppression remains relevant, even in presence of low serum testos­terone and androgen-independent disease

Chemotherapy and Hormone-Refractory Prostate Cancer (HRPC)

Dr. Oh

State of chemotherapy: older chemotherapy regimens (eg, mitoxantrone and vinblastine) achieved 30% response rates (measured by PSA declines); taxanes (eg, paclitaxel and docetaxel) doubled response rates; New England Journal of Medicine (NEJM) study  —  patients had metastatic HRPC; paclitaxel administered every 3 wk compared to mitoxantrone (control arm); paclitaxel group experienced 24% reduction in mortality, compared to control arm; 27% survival advantage at 2 yr, with median survival advantage 14%; this result first ever demonstration of survival advantage in HRPC; no single group of patients benefitted most; taxane drugs associated with increased pain re­mission in »33% of patients, and »50% of patients had major decline in PSA levels; both regimens performed poorly against soft tissue metastases; conclusion  —absolute survival benefits modest; relative survival benefits sig­nificant (»25% reduction in mortality)

Antiangiogenesis: prostate cancers exhibit significant vascular involvement; National Cancer Institute (NCI) study  —  phase II randomized trial compared docetaxel (Taxotere) to docetaxel plus thalidomide; response rates (measured by PSA) comparable; men receiving thalidomide had increased survival, (median £25 yr); thalidomide not considered ideal therapy due to associated neuropathy and availability of better angiogenesis inhibitors; CALGB 90006  —  evaluated bevacizumab plus docetaxel as first-line therapy; combination achieved significant PSA response in patients with high-risk metastatic disease; moderate response rates achieved in patients with soft tissue metastases

Traditional chemotherapy agents: used when patients progress on taxanes; mitoxantrone demonstrates »20% re­sponse rates as second-line therapy (in patients previously receiving docetaxel); MD Anderson Cancer Center study  —  randomized comparison of 4 different regimens; paclitaxel (Taxol) with carboplatin arm demonstrated greatest number and proportion of treatment responses; picoplatin  —  second-generation platinum drug; low rates of renal and neurologic toxicity; 20% typical response rate; combination of picoplatin and docetaxel resulted in signif­icantly higher response rates (»69%)

Experimental agents: ixabepilone  —  commercially available and approved for breast cancer; functions as epothilone analogue and demonstrates activity in patients with resistance to taxanes; therapy associated with 50% rate of PSA response, 30% rate of measurable response; commercial development ceased after failure to demonstrate superior­ity to docetaxel and mitoxantrone and associated neuropathy; denosumab  —  novel bone-directed therapy; functions as receptor activator for nuclear factor (RANK) ligand inhibitor; data not yet presented for prostate cancer, but demonstrates significant activity with breast cancer; possible successor to zoledronic acid; radium  —small random­ized trial in Lancet demonstrated significant survival increases in patients with metastatic HRPC

Novel Therapy: Are We Making Progress?

Eric J. Small, MD, Professor and Interim Chief, Division of Hematology and Oncology, University of Califor­nia, San Francisco, School of Medicine

Cytostatic vs cytotoxic: many novel therapeutics cytostatic, ie, halt progression rather than destroy cells; cytostatic drugs often fail to produce raw survival advantages, making them difficult to study; drug manufacturers typically demand therapeutic response in presence of high disease burdens; in contrast, cytostatic drugs frequently perform better with lower disease burdens; many potential therapies initially tested with early-stage disease, with definitive trials conducted on patients with advanced-stage disease

New uses for chemotherapy: 2 studies demonstrated increased survival rates with docetaxel vs mitoxantrone in met­astatic prostate cancer; Pre-surgical Study Utilizing Neoadjuvant Chemotherapy (PUNCH)  —  ongoing study evalu­ating docetaxel in high-risk cases of localized prostate cancer; compares docetaxel plus hormones to no additional treatment or immediate surgical intervention

Immunotherapy: antigen-presenting cells (APCs)  —  form basis of tumor rejection by scavenging antigens from dead cells; APCs transport scavenged antigens to T-cell receptors, facilitating potential T-cell activation; cytotoxic T-lymphocyte antigen 4 (CTLA4) acts as primary inhibitor of T-cell activation; granulocyte-macrophage colony-stimulating factor (GMC-SF)  —stimulates dendritic cells, offsetting inhibitory immunologic processes; infre­quently produces extremely strong responses; GMC-SF approved by Food and Drug Administration (FDA) for bone marrow reconstitution (after chemotherapy), but not prostate cancer therapy; patients receiving GMC-SF should avoid surgery due to  elevated leukocyte counts; in GMC-SF treated patients, staining shows specific T cells reacting to specific new antigens which have now been cloned; vaccines being developed; ipilimumab  —  single dose removes T-cell inhibition by interfering with CTLA4 activity; dose-escalating ipilimumab plus GMC-SF pro­duced 50% response rates (at highest dosages); all patients had castration-resistant disease (progressed through all stages of hormone therapy); trials now in phase II; sipuleucel-T (Provenge)  —novel vaccine enhances function of dendritic cells in immune-stimulating processes; therapy consists of antigen cassette formed by linking prostatic acid phosphatase (PAP) to GMC-SF; GMC-SF facilitates increased uptake of PAP antigens by dendritic cells; pa­tients undergo plasmapheresis to collect dendritic cells, which are cultured in presence of antigen cassettes; den­dritic cells subsequently reinfused into patient; reinfused cells display PAP antigens on surfaces; FDA approval denied, citing failure to delay disease progression in phase III trials; 3-year survival rates increased to 34% (11% for placebo)

Castration resistance: tumors from patients with benign prostatic hypertrophy (or untreated prostate malignancies) evidence relatively few androgen receptors; staining prostate tumors after hormone therapy reveals massive ampli­fication of androgen receptors ( £10,000-fold); cells with multiplied androgen receptors extremely sensitive and re­quire only minimal hormones to maintain proliferation; in patients on LHRH agonist, adrenal glands continue to produce testosterone; steroid synthesis chain  —  when cholesterol converted to pregnenolone, 3 significant meta­bolic pathways are activated, 1) mineralocorticoid 2) glucocorticoid 3) androgen; ketoconazole inhibits all 3 meta­bolic pathways; abiraterone  —acetate therapy; more targeted (ie, bypasses mineralocorticoid pathway), thus producing fewer undesired effects; in phase I studies, 50% of patients experienced rapid PSA declines (to undetect­able); abiraterone maintains activity longer than ketoconazole; being developed in castration-resistant patients who have failed taxane therapy; physiologic place for abiraterone after hormones and before chemotherapy; may be ad­ministered in office

Suggested Reading

Barry MJ et al: The rising prevalence of androgen deprivation among older American men since the advent of prostate-specific anti­gen testing: a population-based cohort study. BJU Int 98:973, 2006; Berthold DR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Journal of Clinical Oncology 26:242, 2008; De Jager RL et al: Results of a phase II study of picoplatin with docetaxel and prednisone in first-line treatment of castration-resistant prostate cancer (CRPC). Journal of Clinical Oncology ASCO Annual Meeting Proceedings (Post-Meeting Edition) 27:5140, 2009; DeVita VT: The Provenge decision. Nature Clinical Practice Oncology 4:381, 2007; Fong L et al: Neoadjuvant immunotherapy for prostate cancer with GM-CSF and tumor infiltration by antigen presenting cells. Journal of Clinical Oncology ASCO Annual Meeting Proceedings (Post-Meeting Edition) 26:3063, 2008; Greenspan SL et al: Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer. Ann Intern Med 2008 146:416, 2008; Page ST et al: Persistent intrapros­tatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab 91:3850, 2006; Ryan CJ et al: Angio­genesis inhibition plus chemotherapy for metastatic hormone refractory prostate cancer: history and rationale. Urologic Oncology: Seminars and Original Investigations 24:250, 2006; Ryan CJ et al: Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: An early predictor of relapse or incomplete androgen suppression. Urology 68:834, 2006; Shahinian VB et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154, 2005; Small E et al:  Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in pa­tients with hormone-refractory prostate cancer. Journal of Clinical Oncology ASCO Annual Meeting Proceedings (Post-Meeting Edi­tion) 24:4609, 2006; Small EJ et al: Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). Journal of Clinical Oncology 22:1025, 2004; Smith MR et al: Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol 179:152, 2008; Stanbrough M et al: Increased expression of genes converting adrenal androgens to tes­tosterone in androgen-independent prostate cancer. Cancer Research 66:2815, 2006; Thall PF et al: adaptive therapy for androgen-in­dependent prostate cancer: a randomized selection trial of four regimens. JNCI 99:1613, 2007.