Treatment of Metastatic Prostate cancer: How Urologists Should

Sequence Available Agents

INTRODUCTION :Prostate cancer is the most commonlly diagnosed non-cutaneous malignancy among men in the United State. Represented the second leading cause of cancer death in men and nearly 10% of cancer deaths in the U.S. With the advent of PSA. based screening the overwhelmingmajority of patients are diagnosed with clinically localized disease amenable to defenitive surgery or radiation with curative intent.We discuss the practical considerations of the treatment of advanced Pca.While hormonal ablation remains the cornerstone of therapy. We focus on treatment that address survival end points and not the agents that modulate bone health or quality of life.

FIRST LINE HORMONAL THERAPY FORMETASTATIC PCA

with ADT, thereby suppressing its transactivation potential and preventing androgen driven disease progression Strategies include surgical casration‘chemical castration via gonadotropin releasing hormone agonists or antagonists. combined androgen blockadeThe biochemical goal of ADT(androgen deprivation therapy) is to deprive the androgen receptor of its legand and /or blok legand mediated interactions of AR with the use of antiandrogens and lnrermittent androgen suppression.

LHRH agonists vs antagonists: The mainstay of hormonal therapy is suppression of testicular androgen production via depot administration of agents inhibiting the pituitary/luteinizing hormone signaling axis.LH releasing hormone agonists are peptidg analogues of LHRHwhich initially stimulate pituitary secretion of LH, resulting in a brief surge in testosterone (T) production(the so called'flare response “).Under continued stimulation, pituitary expression of LHRH receptors is down-regulated, leading to loss of'LH-secretion and a decline in testicular androgen production by 14 to 21days. LHRH antagonists, which directly inhibit pituitary LH secretion, have been developed to more rapidly suppress androgen levels without inducing the flarephenomenon.

Currently approved LHRH agonists include

1- buserelin (Suprefact, Suprecor)2-leuprolide (Lupron, Eligard)3-nafarelin (Synarel) 4-histrelin (Supprelin LA, Vantas)5-goserelin (Zoladex)6-deslorelin (Suprelorin, Ovuplant) 7-Triptorelin (Pamorelin LA).These medications can be administered intranasally, by injection, or by implant. Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 1 to 12 months.

Currently approved LHRH antagonists include 1-Cetrorelix2-Ganirelix3-Abarelix4-DegarelixGnRH antagonists are administered by either intramuscular injection (abarelix) or subcutaneous injection (cetrorelix, degarelix and ganirelix).

With the withdrawal of abarelix due to a 1% incidence of anaphylaxis,the introduction of degarelix a minimal histamine response. has spured re evaluation of this question. The phase III noninferiority study of degarelix vs leuprolide in -600 patients ,demonstrated more rapid suppression of LH, follicle-stimulating hormone T and PSA levels, without evidence of T surge (>95% of patients reaching castrate T levels by day 3 and >80% within 24 hours in other studies). Degarelix was associated with a lower risk"of-PSA failure and a more sustained reduction in levels of serume alkaline phosphatase (a marker of bone turnover in patients with skeletal metastases) in the subset of patients with baseline PSA >50 ngldl or metastatic disease.

These findings are hypothesis generating regarding a superior clinical benefit of LHRH antagonists particularly as patients with metastatic PCs today have less extensive disease compared to the era when LHRH agonists were introduced. Interestingly ,LHRH antagonist have been reported to induce durable androgen suppression in patients in whom LHRH agonists did not maintain castrate (<50 ng/dl) serum T levels and may be of value in this setting.

Monitoring of serum testosterone levels for LHRH analogue resistance

Failure to maintain T levels <50 ng/dl has been reported in l2% to 25% of men receiving LHRH agonist therapy, with more than 30% failing to achieve T levels <20ng /dl which approximates surgical castration. The etiology of resistance is unclear but may be related to granulomatous injection site reactions disrupting sustained drug release or to upregulated expression of pituitary LHRH receptors in men with metastatic cancer the risk of death was correlated with serum T level >50 ng/dl at 6 months. These data suggest that maintenance of serum T levels <50 ng/dl should be periodiqally ascertained and verified at disease progression before macking a desgnation of CRPC.

Combined androgen blockadeADT can be administered as monotherapy with LHRH analogues or in combination with antiandrogens The rationale for CAB (combined androgen blockade). intended to inhibit testicular and adrenal anderogen activity, is the well substantiated hypothesis that despite testicular androgen ablation, tumoral uptake of circulating adrenal androgens can lead to generation of T and DHT, resulting in continued AR signaling .To date, randomized studies of CAB have been inconclusive and the therapeutic advantage of CAB for advanced PCa remains debated. A central problem is lack ofdata on target activiry. In particular, the currently available nonsteroidal AAs are relatively poor competitive AR antagonists, with affinities for AR that are 50 to 100times lower than the affinity of DHT for AR.

Given the relativelly, small-OS (overall survival),benefit, coupled with increased costs and potential side effect associated with AA. CAB is generally reserved for the early flare period or at the time of disease progression on ADT monotherapy.

Multitargeted androgen blockadeThe poor affinity and potential agonist activity of nonsteroidal AAs strongly suggest that failure of CAB to demonsrate substantial clinical benefit is due to lack of effective agent targeting the AR-axis rather than failure of the concept. The efficacy of CAB may be improved by multitarget androgen blockade incorporating an LHRH analogue and a nonsteroidal AA with aSRD5A inhibitor to inhibit intratumoral conversion of T to DHT. The reduction of intraprostaticDHT levelsby SRD5A inhibitor alone (75% by fenasteride and >90% by dutasteride) approaches or exceed the 75%reduction achieved with testicular anderogen inhibition.

intermittent androgen suppression:(IAS)Cyclic administration of ADT has been evaluated with the goal of delaying progression to CRPC, and mitigating costs and toxicities of continuous androgen deprivation. Patients treated with IAS had reduced hot flashes but otherwise no differences in adverse events including myocardial events or osteoporotic fractures. This trial was the first to report that IAS is not inferior to CAD with respect to OS in men with PSA recurrence after radical therapy. In general, induction consists of 6 to 9 months of LHRH monotherapy or CAB, with discontinuation at PSA nadir <4 ng/ml . Reinitiation is generally considered at PSA10 to 15 ng/ml (4 ro 6 ng/ml in patienrs with relapse afrer radicaltherapy) if the PSA doubling time decreases to 4 to 6 months or at clinical progression. It is not yet recommended as standard of care by organizations such as the American Society of Clinical Oncology or the National Comprehensive Cancer Network.

Timing of ADTfor metastatic PCa:A subset analysis revealed patients with baseline PSA >50 ng/ml had a 3.5-fold increased risk of death from PCa vs those with baseline PSA<8 ng/ml. Of patients with PSA 8 to 50 ng/m1 those with PSADT(PSA doubling time) greater vs less than 12 months had 47.6% vs 11.4% risk of PCSM(prostate cancer specific mortality), at 7 years, respectively. These data suggest that patients with serum PSA>50 ng/ml or PSADT <12 months present a significantly increased risk of dying from PCa and should be considered for early initiation of ADT, while trearment (and toxicity) may be reasonably delayed in men with lower risk disease.

SECONDARY HORMONAL MANIPULATIONA substantial body of evidence suggests that castration resistant tumors are not, in fact, androgen independent but occur in a setting of continued AR mediated signaling driven by residual tumoral or adrenal androgens.The initial therapy of CRPC includes AA withdrawal, high dose bicalutamide, alternative AAs such as flutamide or nilutamide (after progression on bicalutamide), SRD5A inhibitors such as finasteride or dutasteride, the nonspecific CYP17A inhibitor and adrenolytic agent, ketoconazole, estrogenic agents such as DES or transdermal estradiol, the synthetic progestin megestrol acetate and palliative glucocorticoids. Therefore, the choice of agent and sequence is largely empiric and physician dependent, and often driven by side effect profiles of each agent.

Practical treatment considerattons in secondary- hormonal manipulation

Important considerations include the management of known toxicities,which primarily include hepatotoxicity with nonsteroidal AAs and ketoconazole, the necessity for steroid replacement when using ketoconazole and significant risks of thrombosis in patients taking oral estrogens. Liver enzymes should be measured before therapy, monthly for 3 to 4 months and periodically thereafter. Ketoconazole is associated with nausea and hepatotoxicity (especially at the higher doses used for impending cord compression and/or urinary obstruction), and must be given with replacement steroids (typically 20 mg and 10 mg hydrocortisone in the morning and evening, respectively). DES increases in risk of cardiovascular events, including myocardial infarction, stroke and pulmonary emboli.

Predictors of response to secondary hormonal suppression

Circulating adrenal androgen and T levels have been identified as potential predictors of response to secondary hormonal suppression and PSA response. These observations suggest that androgen levels may be useful for stratifying patients likely to sustain durable benefit from second linetherapies from those who should be considered for earlier initiation of chemotherapy or enrollment in clinical trials.

NOVEL HORMONAL AGENTS TARGETING THEANDROGEN AXIS IN CRPC

Accumulating evidence suggests that CRPC remains a ligand and AR driven disease, and that residual tumor androgens play a prominent role in mediating CRPC progression. AR pathway, such as abiraterone and MDV3100.

Abiraterone:generally suppressed serum DHEA(dihydroepiandrosterone), levels by approximately 75%, and DHEA-S, AED(androstenedione), and T to essentially undetectable.It demonstrate a transient increase in bone scan intensity at3 months after starting_abiraterone, with improvement or stability of findings at 6 months. These were generally mild (grade 1 to 2 hypertension, hypokalemia, edema and fatigue) and responded to eplerenone or low dose glucocorticoids (spironolactone should be avoided due to potential ARagonist activity). Decreases in cortisol (twofold) with elevations in ACTH (fivefold) were also observed so addition of steroid to decrease ACTH

MDV3I00: MDV3100 is a competitive AR antagonist that binds rheAR with fivelold to eightfold greater affinity than bicaluramide and only two to threefold lower affinity than DHT. The mosr common adverse events were fatigue, nausea, dyspnea, anorexia and back pain.

CHEMOTHERAPY FOR METASTATIC. CRPCSignificant gairs have been made in the use of chemotherapy for metastatic CRPC for which estramustine, mitoxantrone, docetaxel and cabazitaxel are now approved. Although clinical benefit with agents such as ixabepalone and satraplatin has not been realized.

Docetaxel:every 3 weeks was approved for first line chemotherapy in men with CRPC in 2004 based on 2 phase III studies demonstrating improvements in OS. docetaxel every 3 weeksor mitoxantrone every 3 weeks, all in combination with twice daily oral prednisone for. Significant improvements in OS were demonstrated in men receiving docetaxel every 3 weeks vs mitoxantrone 10 cycle.

Cabazitaxel: Cabazitaxel is thought to be effective for docetaxel resistant tumors via decreased sensitivity to p-glycoprotein mediated drug resistance.

Predictors of survival of men undergoing chemotherapy for CRPC:

Prognostic factors in men initiating first line chemotherapy include visceral metastases, pain, anemia, progression on bone scan or prior use of estramustine. Post-chemotherapy predictors included duration of first line therapy, number of progression factors (pain, PSA or radiographic progression) and whether progression occurred during or- after completing chemotherapy. The number-of progression factors was highly associated with survival, with median survivals of 15.9, 13.2 or 8.0 months for patients with disease progression based on 1,2 or 3 factors, respectively.

Timing of chemotherapy for metastatic CRPC: Although rapidly progressive or symptomatic disease is a clear indication for initiating chemotherapy, the optimal timing of therapy in men with asymptomatic disease remains debated. While the indication for mitoxantrone plus prednisone for CRPC is symptomatic bone pain. Importantly, the magnitude of benefit associated with docetaxel treatment for CRPC was independent of age, performance status, baseline PSA (median 114 ng/ml in TAX-327 and 84 ng/mt in SWOG 9916)or presence of symptomatic disease, suggesting that delaying chemotherapy until symptomatic progression does not decrease clinical benefit. Therefore, initiation of chemotherapy in asymptomatic men may be reasonably delayed until parameters such as high PSA levels, PSADT <4 to 6 months and radiographic progression suggest onset of symptomatic disease is likely.

Increasing PSA or pain flares within the first few months of therapy should not be criteria for discontinuation, and a minimum of 9 to 12 months of therapy is recommended to maximize recognition of response.

IMMUNOTHERAPY FOR METASTATIC CRPCA number of immunological based strategies for PCa have been studied,including the sipuleucel-T (APC 8015), PROSTVAC-VF and GVAX vaccines.

Sipuleucel-T: Sipuleucel-T is an autologous dendritic cell vaccine derived via leukopheresis, ex vivo activation and then re-infusion of a patient's peripheral blood mononuclear cells. Activation is accomplished by incubating blood cells with granulocyte macrophage colony stimulating factor (an immune cell activator) and PAP(prostatic acid phosphatase), expressed by -95% of PCa. Uptake and processing of PAP by dendritic cells activate them so that once re-infused, they stimulate the immune system, generating activated T cells that proliferate and attack tumor cells expressing PAP. Patients undergo'pheresis 3 times at 2-week intervals, with reinfusion of the activated dendritic cells within 2 to 3 days. The primary side effects were minor flu-likesymptoms including grade 1 to 2 chills, fever, headache and myalgias,which resolved by day 2 following the infusion and were slightly morecommon after the second and third infusions.

Timing of immunotherapy for CRPCAn important consideration is the potential to exploit interactions with chemotherapy and/or ADT,both of which alter the exposure and interaction with tumor antigens of the immune system. At present, therefore, sipuleucel-T may be considered for patients with CRPC and asymptomatic or minimally symptomatic metastatic disease. This agent represents a particularly attractive option compared to early chemotherapy as it is rapidly delivered with minimal side effects. In addition, 18% of patienrs in the IMPACT study had received docetaxel, and sipuleucel-T may represent a viable option for minimally post-chemotherapy symptomatic patients with life expectancies greater than 6 months. Conversely, patients with large tumor burdens, those with multiple prior chemotherapy regimens and those without indolent disease are less likely to respond to immunotherapy.