Managementul cancerului de prostată rezistent la castrare

Prostate cancer (PC) is one of the most common cancers in countries with high life expectancy because the risk gradually increases with age. The incidence of PC in the European Union is 78,9/100.000 inhabitants/year, and the mortality rate is 26/100.000 inhabitants/year. The average age at diagnosis is 71 years. In cases of death by non-cancer causes, autopsy revealed a localized PC in 8% of the men aged between 20 and 29 years and in 83% of the ones aged between 70-79 years.

Screening healthy men by means of prostate specific antigen (PSA) increases PC incidence and determines overdiagnosis. Subclinical forms of prostate cancer are common in men over 50 years old. According to recent studies, the effect of intense screening and early treatment on mortality rates remains controversial.

The best-known risk factors for PC are: age, family history (risk increases two times if a first degree relative suffers from PC), race (in the US, the incidence is higher in black people than in Caucasians), geographical location (low incidence in Asia, high incidence in Scandinavia and US) and nutrition (increased animal fat intake is a possible risk factor, but its role has not been fully established in the ethiology of PC).

In patients where PC is suspected, serum PSA should be assessed and a digital rectal examination (DRE) should be performed. Deciding whether to perform a prostate biopsy or not should be based on PSA level, DRE results, prostate size, race, age, comorbidities, patient’s will, and, if available, results from previous biopsies. The prostate biopsy should be guided by trans rectal echography and at least eight tissue samples should be collected.

In terms of histology, the vast majority of prostate neoplasms are adenocarcinomas (95%). 70% of the prostate adenocarcinomas arise in the peripheral zone, 20% in the transitional zone and 10% in the central zone.

A well-performed prostate biopsy allows the pathologist to assess the Gleason score, which is essential for determining prognosis and management.

In 1941, Huggins and Hudges discovered that prostate tumours are almost entirely hormone-dependent. Initially, hormone therapy (HT) was used in advanced stages of PC, when the patient had symptoms or metastases diagnosed by imaging studies.

Currently, androgen deprivation therapy (ADT) is the treatment of choice for all stages of PC; ADT is also used as a neoadjuvant or adjuvant treatment before or after radiotherapy.

ADT lowers both PSA values and tumour size, and long-term therapy leads to a clinically stable interval when PSA values are lower than 4 ng/ml. No hormonal therapy is superior to another!

Patients are monitored by means of serum PSA and regular imagistic studies. The duration of treatment response is, on average, between 12 and 18 months; 20% of the patients still have a complete response after 5 years.

However, a subpopulation of prostate tumour cells acquires resistance to anti-androgen therapies and becomes dominant, resulting in hormone resistance (resistance to castration).

Castration resistant prostate cancer

Definition

Castration resistant prostate cancer (CRPC) is defined as the stage where the disease progresses despite maintaining serum testosterone values at “castration” level (either by surgery or hormonal therapy), which is considered by most experts to be <50 ng/dL.

Diagnosis:

CRPC is diagnosed by one or more of the following criteria:

• increase in plasma PSA levels: most of the patients exhibit a rise in PSA even if the testosterone level is kept <50 ng/dL, which is considered the castration level. The transition to CRPC is defined as an increase in serum PSA of at least 0.2 ng/mL when compared to the previous assessment;
• increase in size of pre-existing lesions/metastases;
• the presence of new metastases.

The increase of PSA serum values, in spite of low plasma testosterone, represents the transition towards the hormone-resistant stage, which is considered lethal for most patients. Clinically, CRPC is diagnosed in the following cases: increasing PSA values in the absence of metastatic disease; newly-diagnosed bone metastases; presence of non-osseous metastases; soft tissue metastases with or without bone damage; node enlargement alone or with concurrent bone and/or visceral metastases. In some cases, new metastases can be diagnosed without increased PSA values. The disease can be symptomatic or asymptomatic. Extra-osseous metastatic disease can develop also in rare sites, such as adrenal gland, kidney, pancreas and brain.

Pathophysiology

In CP, androgens are produced by:

• Leydig testicular cells;
• cholesterol conversion through the cytochrome system;
• prostate tumour tissue (autocrine secretion of androgens).

The conversion of prostate cancer towards CRPC requires the development of adaptive pathways for transmitting the intracellular signal in an androgen-free environment.

The hormone-resistance mechanisms are divided into 6 categories:

• increased expression of enzymes involved in steroidogenesis - studies indicate that in CRPC, even extremely low (castrate) levels of androgens are enough for activating the androgen receptors, and thus for the survival of the tumour cell; moreover, bone metastases contain cells with intact enzymatic equipment, capable of converting adrenalin androgens into testosterone and dihydrotestosterone;
• increased expression of androgen receptors - which is considered a consequence of a genetic modification that promotes an increase in receptor sensibility for androgens, enhancing it at DNA level;
• androgen receptor mutations and changes in the specificity of the receptor for its ligand – this phenomenon results in receptor activation by non-steroid molecules and by anti-androgens (a possible explanation of the paradox effect seen in patients with CRPC when androgen deprivation therapy is discontinued);
• one of the most important mechanisms involved in the development of CRPC is the activation of other pathways for intracellular signal transmission, which can determine an increase in androgen receptor activity or co-activation of the receptor in the absence of androgens. This also includes the activation of other receptors, like the ones for the epidermal growth factor or the tyrosine-kinases receptors;
• alternative intracellular signalling pathways also represent a mechanism involved in the transition to CRPC. This activation can inhibit the apoptosis induced by anti-androgen therapy through Bc1-2 anti-apoptotic protein activation;
• studies have shown that a subpopulation of PC tumour cells is made of undifferentiated stem cells which do not express androgen receptors, and thus they do not depend on androgens for survival.

Treatment

The first step consists in clearly establishing if serum testosterone is actually at “castration” levels. Approximately 1% of the patients undergoing treatment with LH-RH analogues do not respond completely to the therapy and have increased testosterone levels

The second step of the CRPC therapy is deciding if the disease is metastatic or non-metastatic, a feature which will influence therapy.

A. Non-metastatic CRPC

In patients with non-metastatic CRPC, there is an increase in PSA levels, but comprehensive imaging evaluation cannot detect the presence of metastases.

For these patients (usually on androgen deprivation therapy, such as Gosorelin/Leuprolid Acetate), their current medication can be associated with an androgen receptor antagonist (such as Bicalutamide, Flutamide or Nilutamide), thus obtaining a double androgenic blockade. This regimen can delay disease progression or prevent the occurrence of metastases, though there is no definitive clinical evidence to support this outcome.

If the disease progresses following the LH-RH agonists/antagonists and androgen receptor antagonist combination, discontinuation of androgen receptor antagonists (ARA) can be considered. Following this measure, almost 20% of the patients will have a subsequent decrease of over 50% in plasma PSA levels. Nevertheless, usually, this response is short-lasting, 3-5 months, and it appears 4-6 weeks after therapy discontinuation.

After the beneficial effect of discontinuing ARA therapy has disappeared, when plasma PSA values are increasing once more, LH-RH agonists/antagonists therapy can be associated with:

• ARA - a different drug than the one previously used would be preferred;
• Ketoconazole - a non-specific inhibitor of secondary androgen production; its use requires hydrocortisone supplementation due to risk of adrenal insufficiency. This intervention is associated with a PSA decrease in 35-50% of the patients.

REMEMBER

As long as CRPC is considered non-metastatic, ADT is preferred - various drug combinations; initiating chemotherapy is not recommended.

B. Metastatic CRPC

Maintaining testosterone at castrate levels, even after PC transitions to CRPC, is considered gold standard both in the locally-advanced and the metastatic disease, because androgen receptor and the intracellular androgen levels remain significantly elevated even in hormone resistant PC patients.

Patients will continue the therapy with LH/RH agonists/antagonists. High levels of testosterone, over the “castration” limits, can have detrimental effects. Constant androgenic suppression increases survival for patients with CRPC.

If the LH/RH agonists/antagonists therapy was associated with ARA therapy before transition to CRPC occurs, discontinuing ARA treatment can have palliative effects such as decreasing pain intensity, increasing Hb values and decreasing serum PSA levels. Studies report that medication withdrawal was successful for the following agents: flutamide, bicalutamide, nilutamide, megestrol acetate, diethylstilbestrol, estramustine. The response to discontinuing the anti-androgen medication appears after 4-6 weeks, depending on the half-life of the drug. This response could be attributed to the conversion of the antagonist effect to an agonist one, and it would be connected to the anti-androgen’s half-life. For example, flutamide, with a half-life of 7-8 weeks, will determine a faster response than bicalutamide, which has a longer half-life. Almost 20% of the patients receiving a combined androgenic blockade will have a decrease in PSA values of over 50% if  anti-androgen therapy is discontinued (the percentage of patients varying between 15% and 33%), although this response will persist for only 3-5 months.

If no response to ARA therapy interruption is record­ed, another drug from the ARA class can be given in combination with the LH/RH agonist/antagonist. Historically, useful drugs included: diethylstilbestrol (DES) 1 + 3 mg/day, estramustine (the first agent indicated in CRPC) and other parenteral formulas which determined short-term response rates ranging from 24% to 42%.

10 mg/day of Prednisone has proved to have a palliative effect on symptoms for CRPC patients. Hydrocortisone 30-40 mg/day or Dexamethasone 0.5-40 mg/day treatment has a response rate of 16-59%. Most studies report that steroid therapy has demonstrated a decrease in PSA levels, which is associated with increased survival.

REMEMBER

Long-term oestrogen therapy is associated with an increased thromboembolic risk, even for transdermal drugs.

Androgen biosynthesis inhibitors

Ketoconazole is an non-specific inhibitor of secondary androgen synthesis, which includes both synthesis in the adrenal cortical and tumour androgen production, two mechanisms that are related to hormone resistance. It is an imidazole with antimitotic action (when in high doses), that inhibits the CYP17 and CYP11B1 complexes, which are responsible for the function of steroidogenesis enzymes and the modulation of retinoic acid metabolism. Ketoconazole 60-1200 mg/day, associated with hydrocortisone (to lower the risk of adrenal cortical failure), can determine a decrease in PSA values for 50-70% of the patients with response rates correlated with serum levels of androgens. Keto­conazole can also be associated with anti-androgen therapy, but its side effects make it difficult to be tolerated. When used alone, Ketoconazole must be associated with hydrocortisone to compensate the side-effects of blocking steroidogenesis and the occurrence of adrenal cortical failure.

Attention! Ketoconazole must be administered before meals or with juice, in order to ensure a highly acidic gastric environment, which is necessary for a complete absorption. Simultaneous therapy with proton pump inhibitors or H2 antagonists will reduce Ketoconazole absorption. Tumour progression during Ketoconazole therapy is, most often, secondary to increasing androstenedione and dihidroandrostendion (DHEA) sulphate, which favours alternative ways of hormonal metabolism.

Currently, Ketoconazole tends to be replaced with abiraterone acetate.

Abiraterone acetate (Zytiga®), a pregnenolone analogue, is a selective and irreversible inhibitor of steroidogenesis that inhibits cytochrome P450, thus reducing extragonadal testosterone synthesis (including testosterone precursors, dehydroepiandrosterone and androstenedione) in the adrenal gland and malignant cells from prostate cancer; it is more effective than Ketoconazole. The side effects are due to mineralocorticosteroids excess and include: hypertension, fluid retention, oedema, convulsions, headache, muscle weakness, diarrhoea, hypokalemia. In 2010, it was introduced in the treatment of CRPC after Docetaxel chemotherapy. Currently, Abiraterone acetate (1000 mg p.o./day) with prednisone (5 mg x 2/day) is approved as standard therapy in hormone-resistant prostate cancer. Also, Abiraterone has shown to relieve pain and improve the quality of life in patients who previously received chemotherapy.

Next-generation androgen receptor inhibitors

Enzalutamide (Xtandi®) shows a high affinity for blocking the androgen receptor (AR) and inhibits the activated receptor translocation and, implicitly, its binding to the DNA. Enzalutamide impairs AR co-activating factors recruitment and DNA transcription of AR. Enzalutamide therapy is not associated with adverse effects that are specific to the androgen receptors antagonists mentioned earlier.

The phase III study that led to approving enzalutamide for patients with progressive disease after Docetaxel has demonstrated an increase in survival with 4.8 months and a 37% decrease in  mortality; also, enzalutamide was associated with an increase of progression-free survival from 2.9 months to 8.3 months. Recently, a phase III randomized study (PREVAIL) reported favourable results for enzalutamide (160mg/day) treatment in patients with CRPC and no prior chemotherapy. Enzalutamide therapy was associated with: 50% decrease of PSA levels (78% vs. 3%), decrease in soft tissues tumour size (59% vs. 5%), longer PFS and increased interval before chemotherapy initiation. Enzalutamide is approved as standard therapy in CRPC since 2012.

Currently, based on the example of enzalutamide, new molecules are tested for multiple effects on androgenic receptors: ARN-509 and galeteron (TOK-001), with multiple effects on AR, including its blocking and degradation.

Immunotherapy

Sipuleucel-T (Provenge®) is a type of cellular immunotherapy produced by combined transfection of an adenovirus (together with granulocytes and macrophage stimulating factor) in activated mononuclear cells collected from the patient through leukophoresis and stored ex vivo with a PAP fusion protein; these cells are then reinjected in the CRPC patient’s prostate. The therapy’s aim is to activate immune cells so that the body generates an anti-tumour, immune mediated, response. Sipuleucel-T has shown a survival advantage over placebo (25.8 vs. 21.7 months); nevertheless, in most patients, it does not modify DFS or PSA values. For these reasons, Sipuleucel-T therapy should, ideally, be followed by another treatment that allows the short-term control of the disease and enables long-term survival improvement. Sipuleucel-T is well tolerated; its side effects include: asthenia, flu syndrome, chills, fever, myalgia and headache, which resolve within 24 to 48 hours from the infusion.

Chemotherapy

Traditionally, prostate cancer is considered chemoresistant. Nevertheless, in 1996, Mitoxantrone was approved to palliate pain secondary to bone metastasis. Mitoxantrone is a synthetic hydroxyquinone, similar in structure with doxorubicin. Treatment with Mitoxantrone does not increase survival, but improves symptoms in metastatic CRPC patients. Standard regimen is 12 mg/m² every 3 weeks; side effects include: vomiting (61%), asthenia (39%), alopecia (29%), anorexia (25%), neutropenia (20%) with febrile neutropenia in only 2% of the patients. Decrease in cardiac function was observed in 5-7% of the patients.

In 2004, Docetaxel is introduced in the therapy of CRPC. Docetaxel acts on the mitotic spindle, which binds to tubulin, stabilizes microtubule formation and inhibits de-polymerization. In a 70 mg/m² dose every 3 weeks, in association with prednisone, it has become the current gold standard in CPRC treatment. This drug offers not only clinical benefits (symptoms palliation), but also delays disease progression and prolongs general survival from 16.5 months (with mitoxantrone/prednisone) to 18.2 months (using Docetaxel and prednisone). Docetaxel is recommended for CRPC patients with progressive disease associated with a high symptom burden. Docetaxel seems a reasonable option for patients with rapidly progressive disease that is documented by objective imaging changes. Associating Docetaxel to other cytostatics did not prove to be superior to mono-chemotherapy.

Attention! In 2014, it has been demonstrated that using Docetaxel therapy in the first line of treatment for PC patients with unfavourable prognostic factors, associated with anti-androgen therapy, gives better results when compared to anti-androgen therapy alone. Thus, associating Docetaxel with anti-androgen therapy increases median survival with 13.6 months in hormone-sensitive PC patients (phase III study E3805 at the National Cancer Institute). Survival benefits obtained by early Docetaxel chemotherapy (75 mg/m²) associated with anti-androgen therapy (57.6 months) compared to androgenic therapy alone (44 months) was considered unprecedented in prostate cancer. Moreover, the median time to clinical disease progression was significantly improved from 19.8 months, in the case of mono-therapy, to 32.7 months by Docetaxel association.
 

Recently, Cabazitaxel (Jeftana®), a semi-synthetic taxane, demonstrated survival benefits compared to Mitoxantrone, in patients with progressive disease following Docetaxel therapy (15.1 vs. 1.7 months).

Palliative CRPC treatment

Bone metastases therapy

PC patients have a high risk of developing bone metastases (MTS), which are associated with an increased incidence of adverse skeletal events (ASE) (from pathological fractures to spinal cord compression). Additionally, ASE risk increases due to anti-androgen therapy and corticosteroid therapy, which are chronically administered to these patients. For this reason, therapies aimed at preserving bone integrity are an essential part of CRPC management.

Bisphosphonates inhibit osteoclast activity to decrease bone turn-over. The only FDA-approved agent for bone MTS therapy in CRPC patients is zoledronate (4 mg i.v. every 3-4 weeks). Studies show a 25% reduction of ASE frequency in CRPC patients treated with zoledronate, with no other survival improvement. Denosumab is a monoclonal antibody that binds to RANKL and alters osteoclast function; although randomized trials showed no statistically significant difference in the frequency of side effects, disease progression or overall survival between denosumab and zoledronic acid, denosumab does not currently have FDA approval for treatment of bone MTS in CRPC.

Radiotherapy is a commonly used therapeutic option for painful bone MTS. Approximately 80% of patients describe pain improvement in the case of vertebral MTS irradiation. Most often, external irradiation of 30 Gy is used, in a single dose (same efficiency as multifractional regimes). Side effects include anaemia and fatigue, reversible most of the time. Radiotherapy must be associated with systemic control of the disease for optimal outcome of irradiated lesions.

Radiopharmaceuticals are a modern therapeutic option that has proved particularly effective in CRPC patients. Due to their preference for actively metabolic bone regions, they will be internalized in large quantities in the tumour and will induce breaks in the tumour DNA strands. The advantage of these agents lies in the fact that they can be administered in the case of generalized skeletal pain and multiple bone MTS. Currently, in the US, 3 radiopharmaceutical agents are approved: strontium 89, samarium lexidronam and radium-223 dichloride.