/1
`
`Secondary Hormonal Therapy for Advanced Prostate Cancer
`John S. Lam, John T. Leppert, Sreenivas N. Vemulapalli, Oleg Shvarts and Arie S. Belldegrun*,t
`From the Department of Urology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
`
`Purpose: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in
`patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal
`agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents
`may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used
`for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer.
`Materials and Methods: A comprehensive review of the peer reviewed literature was performed on the topic of secondary
`hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds,
`gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer.
`Results: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of
`steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a
`greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit
`has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in
`metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show
`promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate
`Cancer Endpoints Workshop were reviewed in the context of developing new agents.
`Conclusions: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary
`hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indica(cid:173)
`tions and their potential side effects.
`
`Key Words: prostate, prostatic neoplasms, hormones, therapy, carcinoma
`
`I n the United States an estimated 232,090 new cases
`
`were diagnosed and approximately 30,350 deaths were
`attributable to this disease in 2005. 1 Up to a third of
`patients treated for localized prostate cancer eventually ex(cid:173)
`perience biochemical recurrence. Most of these patients are
`placed on hormonal therapy with an LHRH agonist. Histor(cid:173)
`ically almost all patients with metastatic disease on primary
`hormonal therapy demonstrate evidence of hormonal resis(cid:173)
`tance after an average of 18 to 24 months. 2 Unfortunately
`after hormone resistance occurs the prognosis in patients
`with metastatic, hormone refractory disease is dismal with a
`median survival of 12 to 18 months. 2 Due to a large subset of
`patients receiving hormonal therapy for biochemical failure
`a significant number of individuals now have AIPC without
`clinical evidence of metastatic disease. These patients are
`often anxious about their disease status and are typically
`highly motivated to receive additional therapy.
`Most urologists are comfortable providing early treat(cid:173)
`ment in patients with progressive disease through strategies
`such as the addition of a nonsteroidal antiandrogen or
`AAWD. However, after these basic hormonal manipulations
`
`Submitted for publication February 1, 2005.
`*Correspondence: Department of Urology, David Geffen School of
`Medicine at University of California-Los Angeles, 66-118 CHS, Box
`951738, Los Angeles, California 90095-1738 (telephone: 310-206-
`1434; FAX: 310-206-5343; e-mail: abelldegrun@mednet.ucla.edu).
`t Financial interest and/or other relationship with Cougar Bio(cid:173)
`technology.
`
`have been exhausted almost all urologists defer to chemo(cid:173)
`therapy. While chemotherapy prolongs survival and im(cid:173)
`proves quality oflife, this strategy is more toxic and ignores
`the potential usefulness of secondary hormonal therapy (see
`Appendix). Secondary hormonal therapies have been shown
`to result in a greater than 50% decrease in PSA in a sub(cid:173)
`stantial percent of patients with AIPC and a prolonged clin(cid:173)
`ical benefit in some (table 1). Despite these benefits
`urologists have been wary of implementing these therapies
`due to fear of toxicities, which have been demonstrated to be
`mild in numerous studies (table 2). Through this review we
`hope to demonstrate that secondary hormonal therapies can
`provide a safe and effective treatment option in patients
`with AIPC.
`
`PROGNOSTIC FACTORS
`
`In most patients with progressive disease in the face of
`castrate levels of testosterone there are 3 potential courses
`of action, namely observation, secondary hormonal therapy
`and chemotherapy.3 Observation while maintaining testos(cid:173)
`terone suppression is acceptable in patients with low PSA,
`prolonged PSA doubling time and no measurable metastatic
`disease. Some patients with metastases who have a low
`disease burden and slowly progressive disease may also be
`candidates for this approach. Prognostic models have been
`developed to assess patients who have progressive castrate
`metastatic disease despite initial hormonal therapy and
`they may be useful for determining whether to advance a
`
`0022-534 7 /06/17 51-0027 /0
`THE JOURNAL OF UROLOGy®
`Copyright © 2006 by AMERICAN UROLOGICAL AsSOCIATION
`
`27
`
`Vol. 175, 27-34, January 2006
`Printed in U.S.A.
`DOI:10.1016/S0022-5347(05)00034-0
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1080, p. 1 of 8
`
`

`

`28
`
`SECONDARY HORMONAL THERAPY FOR PROSTATE CANCER
`
`TABLE 1. Select trials of second line antiandrogens, adrenal androgen inhibitors, alternative steroid hormones
`and estrogenic compounds in AIPC
`
`References
`
`Treatment (dose)
`
`No. Pts
`
`% Greater Than 50%
`PSA Response
`
`Median Response Duration (mos)
`
`Second line antiandrogens:
`Kucuk et al 18
`Joyce et al 17
`Scher et al 16
`Kassouf et al 19
`Desai et al39
`Debruyne et al36
`
`Adrenal androgen
`inhibitors:
`Small et al9
`
`Harris et al40
`
`Millikan et al41
`
`Small et al22
`
`Small et al23
`
`Kruit et al24
`
`Sartor et al42
`
`Alternative steroids:
`Fossa et al 15
`Sartor et al43
`Tannock et al44
`Small et al27
`Kantoff et al45
`
`Morioka et al46
`Saika et al 4 7
`Storlie et al28
`Debruyne et al36
`Estrogenic compounds:
`Oh et al30
`Smith et al 29
`Oh et al30
`Oh et al48
`Small et al49
`Pfeifer et al50
`
`High dose bicalutamide (150 mg/day)
`High dose bicalutamide (150 mg/day)
`High dose bicalutamide (200 mg/day)
`Nilutamide (200 or 300 mg/day)
`Nilutamide (150 or 300 mg/day)
`Cyproterone acetate (100 mg 2
`times/day)
`
`Ketoconazole (400 mg 3 times/day) +
`hydrocortisone + AA WD
`Ketoconazole (200 mg 3 times/day) +
`hydrocortisone
`Ketoconazole (400 mg 3 times/day) +
`hydrocortisone
`Ketoconazole (400 mg 3 times/day) +
`hydrocortisone + AAWD)
`Ketoconazole (400 mg 3 times/day) +
`hydro cortisone
`Aminoglutethimide (1,000 mg 1 time/
`day) + hydrocortisone
`Aminoglutethimide (450 mg 2 times/
`day) + hydrocortisone + AA WD
`
`Prednisone (5 mg 2 times/day)
`Prednisone (10 mg 2 times/day)
`Prednisone (7.5-10 mg/day)
`Hydrocortisone (40 mg/day)
`Hydrocortisone (30 mg 1/daily/10 mg/
`nightly)
`Dexamethasone (1.5 mg/day)
`Dexamethasone (1.5 mg/day)
`Dexamethasone (0.75 mg bid)
`Liarozole (300 mg 2 times/day)
`
`DES (3 mg)
`DES (1 mg)
`PC-SPES (3 caps)
`PC-SPES (6 caps)
`PC-SPES (9 caps)
`PC-SPES (9 caps)
`
`* Greater than 80% decrease in serum PSA.
`
`52
`31
`51
`28
`14
`161
`
`128
`
`28
`
`45
`
`20
`
`50
`
`35
`
`29
`
`101
`29
`81
`230
`78
`
`27
`19
`38
`160
`
`42
`21
`43
`23
`37
`16
`
`20
`23
`14
`29
`50
`4
`
`27
`
`46
`
`31
`
`55
`
`63
`
`37
`
`48*
`
`21
`34
`22
`16
`14
`
`59
`28
`61
`20
`
`24
`43
`40
`52
`54
`81
`
`Not available
`Not available
`4.0
`7.0
`11.0
`3.6
`
`8.6
`
`7.5
`
`Not available
`
`8.5
`
`3.5
`
`9
`
`4.0
`
`Not available
`2.0
`4.0
`2.3
`2.3
`
`Not available
`Not available
`Not available
`4.6
`
`3.8
`Not available
`Not available
`2.5
`4.0
`Not available
`
`patient to chemotherapy as opposed to further hormonal
`manipulations. Factors that correlate with more advanced
`disease, such as poor performance status, low hemoglobin
`and albumin, and high lactic dehydrogenase and alkaline
`phosphatase, have the largest impact on patient survival. 4
`Another model validated the importance of these factors, in
`addition to highlighting the prognostic significance of pri(cid:173)
`mary tumor Gleason score and PSA. 5
`
`CLINICAL TRIAL END POINTS
`
`The selection of appropriate end points in prostate cancer
`clinical trials remains challenging. The United States FDA
`requires the demonstration of clinical benefit or an effect on
`an established surrogate for clinical benefit prior to approval
`of a therapeutic agent. Clinical benefit is considered to be a
`tangible benefit of obvious worth to the patient, such as
`survival prolongation, pain relief or measurable improve(cid:173)
`ment in tumor related symptoms. Trial end points consid(cid:173)
`ered important are survival, time to progression, response
`rates, palliation and patient reported outcomes. A surrogate
`end point is defined as a measurement or sign used as a
`substitute for a clinically meaningful end point that mea(cid:173)
`sures directly how a patient feels, functions or survives.
`
`Transcripts from the 2004 FDA consensus workshop on
`prostate cancer clinical trial end points were recently pub(cid:173)
`lished. 6 Bone scan findings were a solid end point repeatedly
`shown to lead to a decrease in quality of life and survival.
`However, disadvantages using bone scan findings were in(cid:173)
`terreader variability, need for bone scans to be done at the
`same intervals in all study arms to assure comparability, the
`fact that bone scan findings tend to lag behind PSA progres(cid:173)
`sion, heterogeneity among patients with positive bone scans
`and a lack of consensus on whether radiologists interpreting
`bone scans should be blinded to clinical data. The advan(cid:173)
`tages of PSA as a potential end point are simplicity, repeat(cid:173)
`ability, reproducibility and clear association with the
`disease time course. However, changes in PSA values may or
`may not reflect the effect of treatment. Therefore, PSA alone
`is not a valid surrogate for survival. PSA must also be
`viewed as a time dependent parameter rather than as a
`number. However, patterns of PSA change with time are
`complex and parameters such as PSA doubling time may not
`present a full picture of that complexity. Lastly although
`patient reported outcomes are an important part of the
`global assessment of treatment response, they continue to be
`regarded by the FDA as work in progress.
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1080, p. 2 of 8
`
`

`

`SECONDARY HORMONAL THERAPY FOR PROSTATE CANCER
`
`29
`
`TABLE 2. Side effects of select secondary hormonal
`therapies in AIPC
`
`Drug/Side Effects
`
`% Incidence
`
`Adrenal androgen inhibitors
`
`Ketoconazole:
`Skin toxicity (sticky skin only)
`Skin toxicity (sticky skin, easy bruising + dryness)
`Increased liver enzymes
`Nausea/vomiting
`Gynecomastia (breast enlargement + tenderness)
`Fatigue
`Edema
`Rash
`Anorexia
`Aminoglutethimide:
`Lethargy
`Skin rash
`Thrombocytopenia, leukopenia + anemia
`Megestrol acetate:
`Wt gain
`Fluid retention
`Nausea
`Thromboembolic events
`Estrogenic compounds
`
`DES (3 mg):
`Gynecomastia
`Fluid retention
`Cardiovascular side effects
`Thromboembolic events
`
`About 29
`About 20
`4-10
`10-15
`About 15
`6-10
`About 6
`About 4
`About 2
`
`About 41
`About 36
`About 2
`
`12-25
`5-20
`About 7
`3-6
`
`40-55
`12-21
`7-21
`7-17
`
`Investigators have most commonly used post-therapy de(cid:173)
`creases in PSA as a surrogate end point in advanced disease.
`Patients with AIPC treated at Memorial Sloan-Kettering
`Cancer Center with various therapies who had achieved a
`50% or greater decrease in PSA at 12 weeks appeared to
`have a survival advantage over those who did not. 7 Multi(cid:173)
`variate analysis demonstrated that PSA decrease was the
`most significant factor influencing survival, although other
`factors such as tumor burden and extent of bone disease
`were also significant. These results were corroborated by
`9
`trials using secondary hormonal therapies. 8
`•
`
`RATIONALE FOR
`SECONDARY HORMONAL THERAPY
`
`There is currently no consensus on the most appropriate no(cid:173)
`menclature for progressive prostate cancer. 10 In a patient with
`testosterone greater than 50 ng/ml and a tumor that is respon(cid:173)
`sive to castrating therapies there is a general agreement that
`this may be labeled as hormone naive. 11 Measurable progres(cid:173)
`sion of disease despite castrate serum testosterone or progres(cid:173)
`sive disease, as evidenced by at least 1 new lesion on bone scan
`or increasing PSA (minimum 5 ng/ml with 2 consecutive in(cid:173)
`creases of 50%), has been labeled as AIPC, which is resistant to
`castration but sensitive to secondary hormonal manipulations,
`or HRPC, defined as resistant to all hormonal manipula(cid:173)
`tions.11 Most patients present first with increasing PSA and
`clinical or radiographic evidence of disease can be delayed by
`months or years.6
`The biological mechanism of the failure of hormonal ther(cid:173)
`apies is not completely understood but many factors are
`likely to contribute. 12 Throughout the progression of pros(cid:173)
`tate cancer AR continues to be the primary effector of tumor
`growth and progression despite castrate testosterone, even
`in the presence of antiandrogens. Amplification of the AR
`gene is present in HRPC and it has been shown to correlate
`with increased AR protein expression. 12 AR mutations are
`most common in patients with progressive disease despite
`
`treatment with antiandrogen, reflecting the strong selection
`pressure induced by these agents. 12 A practical implication
`of these data is that each antiandrogen may interact
`uniquely with AR. Therefore, it is reasonable that a patient
`progressing while receiving antiandrogen may still respond
`to another member of this class of agents. After hormonal
`therapy alternative signaling mechanisms through AR
`maintain cellular proliferation and survival despite castrate
`testosterone. They consist of mechanisms that occur in a
`ligand dependent or a ligand independent manner. The
`former includes AR mutations, which lead to receptor pro(cid:173)
`miscuity and activation by a range of steroid hormones, and
`amplification of the AR gene. The latter includes AR activa(cid:173)
`tion by nonclassic factors, such as certain growth factors
`(epidermal growth factor, insulin-like growth factor-1 and
`keratinocyte growth factor), receptor tyrosine kinases, acti(cid:173)
`vation of the AKT (protein kinase B) and mitogen-activated
`protein kinase pathways, recruitment of coactivators such
`as ARA70 and alternative signaling pathways.
`The recent finding that an increase in AR expression is
`associated with resistance to antiandrogen therapy may pro(cid:173)
`vide insight into the development of new diagnostic and treat(cid:173)
`ment strategies for advanced prostate cancer. 13 A provocative
`thought is that AR over expression may allow the continued
`growth of prostate cancer cells due to minute amounts of tes(cid:173)
`tosterone undetectable by conventional assays. Current meth(cid:173)
`ods for measuring total testosterone have limitations with
`regard to low concentrations and unresolved questions con(cid:173)
`cerning the active form of the hormone. Development of a
`supersensitive testosterone detection assay may determine
`whether a castrate state has truly been achieved in patients
`with advanced prostate cancer.
`
`ANTIANDROGEN WITHDRAW AL THERAPY
`
`Although it is less frequent than when originally described,
`a biochemical response can be achieved in approximately
`15% to 20% of patients with AIPC on CAB upon antiandro(cid:173)
`gen therapy withdrawal. 2 This was initially described with
`flutamide and more recently with bicalutamide, nilutamide,
`megestrol acetate and DES. Generally, response is observed
`within 2 to 4 weeks after AAWD and the average response
`duration is approximately 5 months, although responses can
`be durable for 2 years or more. The largest prospective series
`showed a greater than 50% decrease in PSA in 13% of
`patients and objective responses in approximately 2% with
`AAWD therapy alone. 9
`
`SECOND LINE ANTIANDROGEN THERAPY
`
`The deferred use of antiandrogen after progression on go(cid:173)
`nadal androgen withdrawal has been shown to produce a
`greater than 50% decrease in PSA in 80% of those with
`localized disease and 54% of those with metastatic disease. 14
`A phase III study of the European Organisation for Research
`and Treatment of Cancer Genitourinary Group indicated a
`50% or greater PSA decrease with deferred flutamide in 23%
`of symptomatic patients with AlPC. 15 However, it remains
`unclear whether changes in PSA in this scenario translate
`into a survival benefit and whether there are differences in
`response to antiandrogens other than flutamide.
`Of castrate patients with AIPC treated with high doses
`(150 to 200 mg) of bicalutamide 20% to 24% have PSA
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1080, p. 3 of 8
`
`

`

`30
`
`SECONDARY HORMONAL THERAPY FOR PROSTATE CANCER
`
`decreases of 50% or greater with most responses seen in
`those who received prior flutamide therapy. 16
`18 These find(cid:173)
`-
`ings can be explained by the longer half-life and increased
`affinity for the AR of bicalutamide. Furthermore, unlike
`flutamide, bicalutamide retains its antagonistic properties
`for the mutant AR. Similar responses to nilutamide follow(cid:173)
`ing flutamide and bicalutamide therapy have been report(cid:173)
`ed, 19 although to our knowledge no reports exist ofresponses
`to flutamide following bicalutamide or nilutamide therapy.
`A prospective study of nilutamide showed sustained PSA
`decreases of greater than 50% in 29% of patients, suggesting
`that this agent can be useful following prior bicalutamide
`therapy. 19
`Until recently antiandrogens were only used as a compo(cid:173)
`nent of CAB but increasing evidence suggests that mono(cid:173)
`therapy with certain antiandrogens
`is an attractive
`alternative to castration based therapy. 20 The early use of
`antiandrogen therapy has raised concern that there may be
`a decreased response to subsequent hormonal manipulation.
`A subset of patients with evidence of disease progression
`from the 150 mg bicalutamide Early Prostate Cancer pro(cid:173)
`gram received second line hormonal therapies, mostly cas(cid:173)
`tration based therapies, ie LHRH agonist, orchiectomy, CAB
`or antiandrogen alone. 21 Approximately 55% of patients had
`a 20% or greater PSA decrease after 3 months or greater of
`second line hormonal therapy.
`
`ADRENAL ANDROGEN INHIBITORS
`
`Ketoconazole (200 or 400 mg 3 times daily) is an antifungal
`that interferes with cytochrome 3A4 and inhibits steroido(cid:173)
`genesis in the testes and adrenal glands. In a pilot study
`patients with progressive disease despite CAB were treated
`with 400 mg ketoconazole 3 times daily and hydrocortisone
`simultaneous with AAWD. 22 Of the patients 55% had a
`greater than 50% PSA decrease with a median response
`duration of 8.5 months. When studied after AAWD, high
`dose ketoconazole resulted in a greater than 50% PSA de(cid:173)
`crease in 62.5% of patients and 48% showed a greater than
`80% PSA decrease. 23 More recently Cancer and Leukemia
`Group B performed a randomized trial of AA WD alone or in
`combination with high dose ketoconazole with replacement
`doses of hydrocortisone. 9 Of patients undergoing flutamide
`withdrawal alone 11 % had a PSA response compared to 27%
`who underwent flutamide withdrawal plus simultaneous
`ketoconazole (p = 0.0002). Objective responses were ob(cid:173)
`served in 2% of patients treated with flutamide withdrawal
`alone compared to 20% of those treated with flutamide with(cid:173)
`drawal plus ketoconazole (p = 0.02). In patients receiving
`deferred ketoconazole following progression after flutamide
`withdrawal PSA and objective responses were observed in
`32% and 7%, respectively.
`High dose ketoconazole is started at a dose of 200 mg 3
`times daily for 1 week and then increased to 400 mg 3 times
`daily thereafter. Hydrocortisone is normally given at 20 mg
`with breakfast and 10 or 20 mg with dinner, and it should be
`ingested with food. The dose may need to be decreased if
`symptoms suggest hydrocortisone excess, ie ankle swelling
`or poor control of diabetes. Ketoconazole should be ingested
`on an empty stomach and if possible in the absence of his(cid:173)
`tamine-2 blockers or antacids since increased gastric pH
`decreases absorption. The most common side effects are
`weakness or lack of strength, gastrointestinal complaints
`
`such as nausea or vomiting, hepatotoxicity, skin reactions
`and a potential risk of adrenal suppression. The principal
`side effects of ketoconazole are related to gastric irritation,
`leading to nausea and anorexia in at least 10% of patients.
`These side effects are due to mild adrenal insufficiency and
`any nausea or loss of appetite usually improves with time.
`While life threatening cortisol deficiency is uncommon, mild
`adrenal cortisol deficiency is common. Of all side effects liver
`damage may be the greatest concern. Patients on ketocon(cid:173)
`azole must have LFTs assessed monthly. Changes in LFTs
`are generally mild to moderate and in most cases they re(cid:173)
`turn to normal without intervention.
`Aminoglutethimide is an adrenal steroid synthesis inhib(cid:173)
`itor that blocks adrenocorticoid synthesis by inhibiting the
`conversion of cholesterol to pregnenolone. A recent study
`showed a greater than 50% PSA decrease in 37% of patients
`with AlPC treated with 1,000 mg aminoglutethimide daily
`and 40 mg hydrocortisone daily with a median duration of
`response of 9 months and median survival of 23 months. 24
`Aminoglutethimide causes lethargy, nausea and skin rash.
`Peripheral edema, hypothyroidism and abnormal LFTs have
`also been reported. Although aminoglutethimide has largely
`been replaced by ketoconazole, it remains an active avail(cid:173)
`able agent and is a reasonable consideration in patients
`requiring a secondary hormonal approach. Aminoglutethim(cid:173)
`ide is started at a dose of 250 mg 3 times daily for 3 weeks
`and then increased to 4 times daily. Hydrocortisone is pre(cid:173)
`scribed in the same manner as high dose ketoconazole.
`Abiraterone acetate is an oral 17a hydroxylase/Cl 7,20-
`lyase inhibitor developed as a mechanism based steroidal
`inhibitor following observations that nonsteroidal 3-pyridyl
`esters had improved selectivity for inhibiting testosterone
`synthesis. 25 A series of 3 dose escalating phase I studies was
`done in the United Kingdom that demonstrated the suppres(cid:173)
`sion of testosterone synthesis with a positive dose response
`correlation in castrate and noncastrate men with prostate
`cancer. 25 In castrate patients testosterone was further de(cid:173)
`creased by inhibiting testosterone synthesis in the adrenal
`glands. In noncastrate patients testosterone synthesis was
`inhibited in the gonads and adrenal glands. The onset of
`testosterone suppression was rapid and it achieved a nadir 2
`to 3 days after initial dosing. Abiraterone acetate appears to
`be well tolerated and to our knowledge no serious side effects
`have been reported. Based on the mechanism of action this
`agent may have advantages over other antiandrogens by
`selectively inhibiting adrenal androgens and consequently
`decreasing serum and possibly intraprostatic testosterone to
`super castrate levels. The current data support the potential
`role of this agent in patients who have become refractory to
`LHRH agonists. To establish the optimal dose and regimen
`for chronic administration a phase I/II study to evaluate the
`safety and efficacy of abiraterone acetate in castrate pa(cid:173)
`tients with chemotherapy na'ive AIPC is under way.
`
`CORTICOSTEROIDS
`
`Glucocorticoid repletion is a standard supportive therapy in
`patients treated with agents that inhibit adrenal function.
`These agents may also have modest anticancer activity and
`numerous studies have added to our knowledge of their
`effects directly or indirectly. An early study suggested that
`corticosteroids are active in patients with AIPC treated with
`daily oral prednisone in doses of 7.5 to 10 mg. 26 After 1
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1080, p. 4 of 8
`
`

`

`SECONDARY HORMONAL THERAPY FOR PROSTATE CANCER
`
`31
`
`month of therapy improvements in quality oflife were noted
`in 38% of patients that were maintained a median of 4
`months in 19%.
`Much data on corticosteroids in prostate cancer comes
`from control arms of chemotherapy studies. In a study eval(cid:173)
`uating the antitumor effects of the antihelminthic agent
`suramin 16% of patients with AIPC treated with hydrocor(cid:173)
`tisone alone had a greater than 50% decrease in PSA. 27
`Similar PSA decreases were reported in 61 % of patients
`treated with 0.75 mg dexamethasone 3 times daily. 28 Corti(cid:173)
`costeroids should be considered active hormonal agents for
`prostate cancer. However, there does not appear to be a
`superior dose or type of corticosteroid that is most effective
`in the absence of a randomized trial. These effects may also
`be short in duration with studies suggesting an approximate
`4-month median duration of response in 20% to 30% of
`patients. 2
`
`ESTROGEN BASED THERAPIES
`
`Estrogens have long been known to have activity in the
`initial management of prostate cancer. DES is an inexpen(cid:173)
`sive synthetic estrogen that decreases testosterone by de(cid:173)
`creasing LHRH secretion as well as directly inhibiting LH
`secretion by the pituitary gland. DES at a dose of3 mg daily
`results in castrate testosterone in 1 to 2 weeks by the inhi(cid:173)
`bition of LHRH production from the hypothalamus. Several
`studies have demonstrated the modest efficacy of estrogens
`in the context of AIPC with PSA responses of26% to 66% at
`1 to 3 mg DES. 29
`30 In a recent study a 21 % PSA response
`•
`rate (50% or greater) was reported in which 3 mg DES daily
`plus 2 mg Coumadin® served as the control arm. 30 DES has
`been used at doses of 1 to 1.5 gm daily for 7 days, followed by
`weekly infusions at the same dose. Response rates have been
`15% to 20% using National Prostate Cancer Project criteria
`to approximately 33% using PSA criteria. These data sug(cid:173)
`gest that estrogen agonists have some activity in patients
`with progressive disease despite antiandrogens and there is
`not likely to be a significant dose response effect with DES.
`DES at a dose of 3 mg daily results in castrate testosterone
`in 1 to 2 weeks by the inhibition of LHRH production from
`the hypothalamus. DES is associated with significant car(cid:173)
`diovascular
`toxicities,
`including myocardial
`infarction,
`stroke and pulmonary embolism, especially at moderate to
`high doses. 2 Anticoagulation with Coumadin® is recom(cid:173)
`mended to prevent these side effects. Other common side
`effects of estrogen therapy are nausea, vomiting, weight
`gain, edema and gynecomastia. Gynecomastia may be de(cid:173)
`creased by prophylactic irradiation of the breasts.
`Estrogen receptors are expressed in prostate cancer cells
`as well as in the stroma in androgen depleted tissues, rais(cid:173)
`ing the possibility that estrogen receptor is actively contrib(cid:173)
`uting to tumor growth and survival. Tamoxifen binds to
`estrogen receptors, acting as a partial agonist/antagonist. It
`has been associated with a response in patients with AIPC
`and in those who were hormone naive. A phase II study of
`high dose tamoxifen (160 mg/m2 daily) in patients with
`metastatic HRPC demonstrated a combined partial re(cid:173)
`sponse/stable disease rate of23%. 31 The antitumor effects of
`estrogen continues to be an area of investigation with mixed
`results seen to date in clinical trials.
`The synthetic oral agent estramustine phosphate so(cid:173)
`dium is formed by the fusion of a nitrogen mustard to an
`
`estradiol moiety. It primarily produces an estrogenic and
`a microtubule inhibitory effect. When used as a single
`agent, estramustine has produced only modest objective
`response rates (5% to 19%). 32 However, recent in vitro and
`in vivo studies demonstrated synergy when estramustine
`was used in combination with other microtubule inhibi(cid:173)
`tors, including vinca alkaloids, etoposide and taxanes.
`Two recent multicenter, phase III studies (TAX 327 and
`SWOG 9916) demonstrated a survival advantage of do(cid:173)
`cetaxel based chemotherapy over mitoxantrone. 33
`34 The
`•
`results of these trials also bring into question the addi(cid:173)
`tional benefit of estramustine to docetaxel. Although no
`definitive comparison between the 2 studies can be made,
`patient characteristics and overall survival in the control
`groups are similar. Overall survival in the investigational
`arms of docetaxel and prednisone every 3 weeks, and
`docetaxel and estramustine suggests that the 2 are equiv(cid:173)
`alent. Therefore, the additional toxicity seen with estra(cid:173)
`mustine :would support the use of prednisone over
`estramustine. Docetaxel is currently the only FDA ap(cid:173)
`proved regimen for metastatic HRPC. Second line hor(cid:173)
`monal therapy should not be used as an option to delay or
`avoid docetaxel in men with symptomatic metastatic
`HRPC who are otherwise candidates for cytotoxic chemo(cid:173)
`therapy. For a more detailed discussion of chemotherapy
`for advanced prostate cancer one can refer to a 2004
`report on prostate cancer of the Prostate Cancer Founda(cid:173)
`tion. 32
`PC-SPES (BotanicLabs, Brea, California) was a popular
`herbal combination of 8 well-defined compounds that was
`commercially available from 1996 to 2002. 30 Several clinical
`studies of PC-SPES in patients with AIPC demonstrated
`estrogenic effects and a greater than 50% PSA decrease in
`52% to 81%. However, synthetic estrogens, DES and ethinyl
`estradiol were detected in various lots of PC-SPES, leading
`to its removal from the market.
`
`PROGESTINS
`
`As with estrogens, the mechanism by which progestins in(cid:173)
`hibit tumor growth is not entirely clear. These agents have
`been shown to suppress gonadotropin and adrenocortico(cid:173)
`tropic hormone secretion. In addition, they may exert direct
`cytotoxic effects. Three progestins have been used to treat
`prostate cancer, namely CPA, megestrol acetate and me(cid:173)
`droxyprogesterone acetate. CPA is a steroidal antiandrogen
`with progestational properties, creating a feedback inhibi(cid:173)
`tion of pituitary LHRH release to suppress testosterone
`production, and direct effects on AR. Several trials of CPA
`have been done in AIPC and it has been shown to decrease
`bone pain with some improvements in performance status. 2
`CPA is generally well tolerated, and edema, weight gain and
`shortness of breath are rarely seen. However, liver toxicity
`has been recognized as a complication oflong-term use. CPA
`is not approved by the FDA for use in the United States.
`Megestrol acetate may contribute effects through LHRH
`suppression and AR blockade, and possibly through 5a-re(cid:173)
`ductase inhibition. Studies of megestrol acetate have shown
`a PSA response in 10% to 15% of patients with AIPC.2
`8
`·
`Several groups have evaluated medroxyprogesterone ace(cid:173)
`tate in AIPC and its primary effect seems to be the relief of
`bone pain. 2 The major side effects of medroxyprogesterone
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1080, p. 5 of 8
`
`

`

`32
`
`SECONDARY HORMONAL THERAPY FOR PROSTATE CANCER
`
`include peripheral edema and an increased risk of cardio(cid:173)
`vascular events.
`
`CALCITRIOL
`(la,25-dihydroxyvitamin D 3 or 1,25(0H)2 D 3 )
`
`Calcitriol, the principal active metabolite of vitamin D, has
`significant antineoplastic activity in preclinical models of
`prostate cancer and many other tumor types. Reported
`mechanisms of activity are the inhibition of proliferation
`and cell cycle arrest, apoptosis induction, increased differ(cid:173)
`entiation, and decreased i