Cancer Investigation
`
`ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
`
`Treatment Options in Androgen-Independent
`Prostate Cancer
`
`Primo N. Lara & Frederick J. Meyers
`
`To cite this article: Primo N. Lara & Frederick J. Meyers (1999) Treatment Options in
`Androgen-Independent Prostate Cancer, Cancer Investigation, 17:2, 137-144, DOI:
`10.1080/07357909909011728
`
`To link to this article: http://dx.doi.org/10.1080/07357909909011728
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`Published online: 24 Mar 2010.
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`JANSSEN EXHIBIT 2053
`Wockhardt v. Janssen IPR2016-01582
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`

`

`Cancer Investigation, 17(2), 137-144 (1999)
`
`I CLINICAL SCIENCE REVIEW
`
`Treatment Options in Androgen-
`Independent Prostate Cancer
`
`Primo N. Lara, Jr., M.D., and Frederick J. Meyers, M.D.
`
`~
`
`University of California Davis Cancer Center
`Division of Hematology-Oncology
`Sacramento, California
`
`Key words: Prostate cancer; Androgen-independent; Hormone refractory;
`Treatment; Chemotherapy
`
`ABSTRACT
`
`Metastatic prostate cancer is a leading cause of cancer-related death in men. Al-
`though most patients will respond to androgen ablation as initial systemic therapy,
`nearly all patients will develop androgen-independent prostate cancer (A1 Cap)
`and will succumb to the disease. Advances in molecular biology have demonstrated
`mutations in and persistent expression of the human androgen receptor in metastatic
`disease. Furthermore, recent evidence indicates that an apoptotic block through p53
`mutations or bcl-2 overexpression may have a potential role in the poor responses
`seen with standard chemotherapy, Presently, the six general treatment options avail-
`able for A1 Cap are best supportive care, radiation therapy, radioisotopes, second-
`line hormonal therapy, chemotherapy (single agent or co~bination~, and investiga-
`rional therapies such as monoclonal antibodies, cyclin-dependent kinase inhibitors,
`matrix metalloproteinase inhibitors, and antiangiogenesis agents, among others.
`None of these modalities have produced durable remissions, although some have
`demonstrated palliative bene$t. The next generation of clinical trials should not
`consist of futile hormonal manipulations or repetitive chemotherapy. Therapeutic
`strategies aimed at circumventing molecular blocks to cell death or targeting unique
`cancer molecules and genes will be more likely to improve quality of life and longev-
`ity. Furthermore, the aggressive use of palliative care will ensure effective caring
`for patients and the healing of families in the absence of cure.
`
`Copyright 0 1999 by Marcel Dekker, Inc.
`
`www.dekker.com
`
`137
`
`

`

`138
`
`Lara and Meyers
`
`INTRODUCTION
`
`MOLECULAR CORRELATES
`
`Prostate cancer (Cap) will kill 39,000 men in the
`United States this year, making it the second leading
`cause of cancer-related deaths in men. The standard treat-
`ment for metastatic disease is androgen ablation, either
`through bilateral orchiectomy or the administration of lu-
`teinizing hormone-releasing hormone agonists. Most pa-
`tients respond as evident by a fall in the levels of prostate-
`specific antigen (PSA), reduction in bone pain, and, when
`present, regression of soft tissue masses. Recently, the
`role of combined androgen blockade (CAB) has been
`questioned after a large, prospective, intergroup, random-
`ized trial failed to show significant improvements in pro-
`gression-free and overall survival in patients receiving
`the anti-androgen flutamide after orchiectomy compared
`with orchiectomy alone in patients with metastatic CaP
`(1). Although initially efficacious, CAB is known to
`cause toxicities such as fatigue, vasomotor instability,
`and muscle strength deterioration. Furthermore, the re-
`sponse to androgen deprivation is brief, with a median
`duration of response of 18 months (2). In those patients
`who receive CAB, a brief clinical response to anti-andro-
`gen withdrawal is well described and is reported in up
`to 30% of patients on chronic treatment (3,4). Presently,
`there is no consensus regarding the most appropriate sec-
`ond-line treatment after the development of such “hor-
`mone refractory,” or more accurately, “androgen-inde-
`pendent” (AI) Cap.
`
`DEFINITION
`
`There is presently no single definition for A1 CaP be-
`cause of the inexact means of determining what consti-
`tutes progressive disease in the face of maximal androgen
`deprivation. At the University of California Davis Cancer
`Center, progression is defined as an increase in the size
`of bidimensionally measurable metastatic disease in bone
`or soft tissues by at least 50% from baseline or a serum
`PSA of at least 10 ng/ml that has risen on three succes-
`sive evaluations. Patients must have documented castrate
`levels of testosterone and must have discontinued anti-
`androgen therapy for at least a month, with one of two
`rising PSA determinations noted after anti-androgen
`withdrawal.
`CaP is thought to recur despite androgen ablation be-
`cause a clone of cells never responsive to maximum an-
`drogen ablation gains a growth advantage or a clone of
`cells with initial partial responsiveness adapts to the new
`milieu.
`
`The role of the human androgen receptor (hAR) in the
`development of A1 CaP has been clarified further in the
`past decade. The hAR is a nuclear steroid hormone recep-
`tor that binds to specific portions of the genome to stimu-
`late transcription of “androgen-inducible genes” (5). A1
`tumors have been demonstrated to continually express
`high levels of hAR gene transcripts (6). Furthermore,
`hAR as detected by immunohistochemistry has been
`found in 100% of distant metastases of CaP (7). Our stud-
`ies at UC Davis have demonstrated that hAR expression
`after CAB is seen preferentially in high-grade high-stage
`tumors (8). In addition, undetectable serum PSA from
`tumors that remain hAR positive may predict relapse
`after CAB. Many mutations in the hAR found in A1 Cap
`have been described and are reviewed elsewhere (9). Al-
`together, these recent findings suggest that most A1 CaP
`cells may potentially have in vivo hormone respon-
`siveness or that an agonist binds to hAR, thus promoting
`disease progression.
`Metastatic prostate cancer has also been shown to fre-
`quently express mutations in the p53 tumor suppressor
`gene (10) and increased expression of bcl-2 (1 l), two im-
`portant cell cycle regulatory genes that modulate the
`apoptotic or programmed cell death pathway. Data sup-
`port that mutations in cell cycle regulation influence both
`the natural history and response to treatment of A1 Cap,
`leading to the development of investigational new cyto-
`toxic agents or the identification of novel molecular tar-
`gets.
`
`TREATMENT OPTIONS
`
`The primary goal of treatment of A1 Cap, as in any
`other malignancy, is cure. In a population of often elderly
`men, symptom palliation and significant prolongation of
`survival (without cure) are important secondary goals.
`Priority should be given to accrual into clinical trials, be-
`cause the current treatment options for A1 CaP have
`largely produced disappointing results.
`The six main options currently available are support-
`ive care, external beam radiation therapy, radioisotopes,
`second-line hormonal therapy, chemotherapy, and inves-
`tigational therapies, including suramin, novel agents, and
`“targeted therapy” such as radiolabeled monoclonal
`antibodies, among others.
`One caveat in assessing response to systemic therapy
`is the evaluation of nonmeasurable disease. Decline in
`the serum PSA has been used as a surrogate marker, but
`
`

`

`Treatment Options for Prostate Cancer
`
`Table 1
`Response Criteria Used in AI Cap Trials at UC Davis
`Cancer Center
`
`Complete response (CR): Complete disappearance of all
`measurable disease with no new lesions and no disease-
`related symptoms. No evidence of nonassessable disease,
`including normalization of PSA and other abnormal lab
`values. For assessable disease using PSA as the primary
`end point, CR refers to normalization of the PSA for three
`successive evaluations (every 3 weeks).
`Partial response (PR): Greater than or equal to 50% de-
`crease under baseline in the sum of products of perpendicu-
`lar diameters of all measurable lesions. No progression of
`assessable disease or new lesions. For assessable disease
`using PSA as the primary end point, a decline of PSA by
`>80% without normalization for three successive evalua-
`tions.
`Stablelno response (SD): Does not qualify for CR, PR, or
`progression. For assessable disease using PSA as the pri
`mary end point, patients who do not meet criteria for PR
`or progression for at least 90-120 days will be listed in a
`stable disease category.
`Progression: 50% increase or an increase of 10 cm2 (which-
`ever is smaller) in the sum of products of all measurable
`lesions over smallest sum observed (over baseline if no de-
`crease) using the same techniques as baseline, or clear
`worsening of any assessable disease, or reappearance of
`any lesion that had disappeared, or appearance of any new
`lesion/site, or failure to return for evaluation due to death,
`or deteriorating condition (unless clearly unrelated to pros-
`tate cancer). For assessable disease using PSA as the pri-
`mary end point, at least two consecutive increases in PSA
`to >50% above baseline, if baseline is greater than five
`times the upper limit of normal
`
`Duration of PSA response should be at least 4 weeks.
`
`lack of consistent criteria prevents direct comparison
`of “PSA response rates” across different clinical trials.
`Table 1 outlines the criteria used by the UC Davis Cancer
`Center in its current trials as approved by the National
`Cancer Institute.
`
`Supportive Care
`
`The biology of prostate cancer unfolds over years. If
`this process ends in A1 CaP, a patient experiences transi-
`tions in medical goals from that of cure to palliation. Pal-
`liative care involves the same or more attention to the
`science and art of caring as the other stages.
`The science includes symptom management, ad-
`vanced directives, and knowledge of resources in the
`
`139
`
`community. For most men, disposition of resources in-
`cluding estate planning is important, and the failure to
`address this issue is a source of significant anxiety.
`The art of palliative care is to recognize the anxieties
`of a life-threatening illness. The care unit is the family,
`however defined by the patient, and the relationships that
`he holds most dear. The existential issues of the meaning
`of life are a rich source of family and physician satisfac-
`tion if sufficient time and reimbursement is allocated.
`Effective palliative care does not exclude the systemic
`strategies discussed below, rather they are by definition
`palliative rather than curative. Importantly for many men,
`investigational therapy is a critical intervention that rep-
`resents efforts at disease control. However, it is also a
`warning that end-of-life issues should be addressed in a
`meaningful way. The failure to do so results in referrals
`to hospice in the last week of life and a lost opportunity
`for a family to honor a man at his life’s end.
`Current reimbursement mechanisms exclude the pro-
`vision of investigational therapy and hospice care. This
`is an irrational policy given the dual needs of patients.
`Until the enlightenment of reimbursement policy occurs,
`physicians who care for these families should recog-
`nize and initiate significant discussions of end-of-life
`issues.
`
`External Beam Radiation and
`Radioisotopes
`
`Both modalities have been demonstrated to be effica-
`cious in controlling pain from metastatic deposits in
`bone. Focal radiation, used before the cortex is eroded
`by greater than 50%, can prevent pathologic fractures
`of weight-bearing bones. If the cortex is significantly
`eroded, orthopedic fixation should precede radiotherapy.
`External beam radiation has been reported to completely
`eliminate bone pain at the treated site in about 40% of
`patients (1 2).
`There are currently three Food and Drug Administra-
`tion-approved radioisotopes: phosphorus-32, samarium-
`153, and strontium-89. Phosphorus-32 was the first radio-
`isotope used for palliation of pain from bony metastases.
`However, extensive osseous uptake (enhanced by pre-
`treatment with testosterone and parathyroid hormone)
`leads to significant myelosuppression (1 3,14). Thus,
`phosphorus-32 has limited clinical usefulness. Samar-
`ium- 153 has been shown to provide significant palliative
`pain relief in 70-80% of patients treated in early phase
`clinical trials, one of which tested the radioisotope across
`different malignancies metastatic to bone (15-17). Dura-
`tion of pain control was brief, lasting an average of
`
`

`

`140
`
`4-8 weeks. Strontium-89, an isotope of calcium, is
`among the most widely used and extensively studied
`radionuclides. It is avidly taken up by osteoblasts. A re-
`cent review has estimated that as many as 80% of patients
`with painful bony metastases achieve some pain relief
`with strontium-89 therapy, with approximately 10% of
`patients becoming completely pain free (1 8). Other radio-
`nuclides are actively under investigation, including rhe-
`nium-186 (19) and tin-l17m (20).
`
`Second-Line Hormonal Therapy
`
`After withdrawal from anti-androgen therapy, some
`patients may benefit modestly from second-line hormonal
`treatment, with a PSA response proportion of 14-75%
`(21). The hormonal agents that have been tested in early
`phase clinical trials include aminogluthetimide (22),
`high-dose bicalutamide (23,24), megestrol acetate (25),
`hydrocortisone (26), prednisone (27), and ketoconazole
`(28), among others. However, objective (measurable) re-
`sponses are unusual (<5%), the duration of PSA re-
`sponse is only 3-4 months, and there is no improvement
`in overall survival.
`Furthermore, in a recent trial there was rapid disease
`progression observed in 11 of 27 previously treated mini-
`mally symptomatic patients treated with second-line bi-
`calutamide at a dose of 50 mg daily (29). This suggests
`the possibility of a “paradoxical stimulatory effect on
`tumor growth possibly associated with a mutant andro-
`gen receptor.” In a trial using bicalutamide at 200 mg
`daily, “clinical benefit” was seen in some patients who
`had previously progressed on prior flutamide therapy
`(23).
`
`Chemotherapy (Single Agent)
`
`Nearly all classes of chemotherapeutic drugs as single
`agents have been used in both controlled and uncon-
`trolled trials for A1 Cap. Most antimetabolites, most al-
`kylating agents (including melphalan, nitrogen mustard,
`cisplatin, and carboplatin), vinca alkaloids, and the
`nitrosoureas have shown little or no activity in this dis-
`ease (30). Objective overall responses produced by these
`agents are generally under 10% (31). As would be ex-
`pected, there is no improvement in overall survival with
`these drugs. However, pain reduction is often achieved
`despite lack of an objective response.
`Among the most widely studied of these agents is es-
`tramustine, an alkylating agent that consists of nitrogen
`mustard attached to estradiol by a carbamate ester link-
`age. Estramustine disrupts microtubule assembly by
`
`Lara and Meyers
`
`binding to microtubule associated proteins, therefore hin-
`dering mitosis (32). In six prospective trials by the Na-
`tional Prostate Cancer Project using estramustine as a sin-
`gle agent, there were 14 objective responses out of 217
`patients, for an overall response rate of 2.8% (33-38).
`More encouraging results were noted when estramustine
`was combined with other agents.
`The alkylating agent cyclophosphamide has also been
`found to have modest activity in A1 Cap. Small trials of
`daily oral cyclophosphamide have yielded overall re-
`sponses rates ranging from 14 to 31% (39-41). Similar
`results were noted with intravenous high-dose cyclophos-
`phamide, with an overall objective response rate of 30%
`(30). Ifosfamide as a single agent has produced disap-
`pointing results (42).
`The anthracyclines doxorubicin and mitoxantrone
`have measurable activity against Cap. A stable disease
`rate of 68% and a partial response rate of 16% (by Na-
`tional Prostate Cancer Project criteria) have been re-
`ported for weekly intravenous doxorubicin (43). Mitox-
`antrone is said to have less cardiotoxicity than its older
`cousin doxorubicin and had been used in many early
`phase clinical trials for A1 Cap. The PSA response rates
`(defined in most trials as a decrease in the serum PSA of
`greater than 50%) to mitoxantrone as a single agent have
`ranged from 13 to 30% (44,45). Clinical activity, defined
`as a reduction in bone pain (46), has led to further studies
`using mitoxantrone in combination with prednisone or
`hydrocortisone.
`Despite broad-spectrum antitumor activity, paclitaxel
`has not been shown to have single-agent activity in A1
`Cap. The Eastern Cooperative Oncology Group con-
`ducted a phase I1 trial of paclitaxel using only bidimensi-
`onally measurable disease for its response criteria (47).
`Only one partial response out of 23 patients was ob-
`served, associated with a greater than 80% reduction in
`the serum PSA lasting 9 months.
`The camptothecins are a novel class of anticancer
`agents that inhibit toposiomerase I. Topotecan, a semi-
`synthetic camptothecin, had a 7.6% response rate in 13
`patients with bidimensional measurable disease and a
`greater than 50% reduction in the serum PSA in 6 of 34
`patients (48). A newer camptothecin analogue, 9-amino-
`camptothecin, has demonstrated promising preclinical
`activity against prostate cancer (49). Phase I1 trials of the
`original dimethylacetamide formulation are nearing com-
`pletion. We are presently conducting a phase I1 trial of
`the colloidal dispersion formulation at the University of
`California Davis Cancer Center in collaboration with the
`City of Hope and University of Southern California Can-
`cer Centers.
`
`

`

`Treatment Options for Prostate Cancer
`
`The novel nucleoside analogue gemcitabine has also
`been evaluated in a recent clinical trial (50). Among 15
`assessable patients, only 13% showed PSA responses,
`and there was no significant change in the Quality of Life
`scores. The authors thus concluded that gemcitabine had
`limited activity in A1 Cap.
`
`Combination Chemotherapy
`
`Estramustine has been tested in combination with
`other known cytotoxic agents such as etoposide (5 1), vin-
`blastine (52), paclitaxel(53), cisplatin (36), and docetaxel
`(54). Differences in trial design and response criteria
`make these trials difficult to compare, but the overall re-
`sponse rates to estramustine-based combination regimens
`run between 10 and 50% (55). Among the most active
`combinations is estramustine plus agents with microtubu-
`lar targets such as vinblastine or paclitaxel. In a represen-
`tative phase I1 trial of the estramustine plus vinblastine
`regimen (52), 40 patients were accrued using PSA, per-
`formance status, pain score, and measurable disease as
`response criteria. No complete responses and only one
`partial response (14%) were observed. There were 11 of
`36 PSA responses (>50% reduction). Oral estramustine
`in combination with paclitaxel (as a 96-hr intravenous
`infusion) produced responses in four of nine patients with
`measurable disease and PSA responses in 17 of 32 pa-
`tients with bone-only metastases (53). Clearly, the con-
`cept of combining two drugs with similar mechanisms of
`action but distinct and unique molecular targets produces
`clinically significant PSA responses.
`Other promising combinations that have been tested
`include doxorubicin plus cyclophosphamide (56) and 5-
`fluorouracil plus cisplatin (57), among others.
`Hydrocortisone with or without mitoxantrone was
`evaluated in 242 patients enrolled in a prospective ran-
`domized' phase 111 trial by the Cancer and Leukemia
`Group B (58). Preliminary results indicate no survival
`advantage in the mitoxantrone plus hydrocortisone arm.
`However, there was improved bone pain palliation and
`PSA reductions in the combination arm. In a prospective
`randomized phase 111 trial of prednisone alone versus
`mitoxantrone plus prednisone, there was a statistically
`significant difference in the duration of palliation in fa-
`vor of the combination regimen (1 8 vs. 43 weeks, p <
`0.0001) (59). Unique to this trial is the establishment of
`palliation as the primary study end point, using validated
`quality of life questionnaires, pain scales, and analgesic
`intake monitoring. Until similarly designed studies using
`different agents mature, this regimen will be part of the
`community standard of care.
`
`141
`
`Investigational Therapies
`
`Suramin, a polysulfated naphthylurea, was recognized
`to be cytotoxic in vitro by virtue of its ability to inhibit
`the binding of several growth factors to their receptors
`(60). In a trial of suramin in 38 patients with A1 Cap, 6
`of 17 patients with measurable disease responded (61).
`There was a PSA response (defined as a decline in the
`serum PSA of >75%) in 38% of the remaining patients
`with bone-only metastasis. Toxicity was considerable,
`with two drug-related deaths and 16 culture-positive bac-
`terial infections observed. After pharmacokinetic model-
`ing and dosing modifications, many phase I and I1 trials
`have since been conducted, yielding objective responses
`between 20 and 70% (62-68). The toxicities observed in
`these later trials, including infection and death rates, were
`considerably less than those earlier reported. The poten-
`tial confounding variables of concurrent hydrocortisone
`(administered because suramin is an adrenocorticolytic)
`and flutamide withdrawal have been addressed in a phase
`I1 trial (69). This study concluded that suramin's anti-
`tumor efficacy in A1 CaP is independent of the therapeu-
`tic effect of hydrocortisone treatment or flutamide with-
`drawal. Suramin continues to be investigated in many
`current clinical trials.
`Tumor-associated antigen expression opens a novel
`avenue for treatment of A1 CaP through the deploy-
`ment of specific antibodies that are coupled to a radio-
`active moiety that delivers its toxic effects only at
`metastatic sites. In a phase I1 trial of such a strategy,
`a specific monoclonal antibody linked to a radioac-
`tive iodine source was tested in A1 CaP (70). In 14
`assessable patients, 11 (77%) had targeting to sites of
`disease with pain palliation in 3 patients. However,
`further dosing was not possible because of the devel-
`opment of human anti-mouse antibody or HAMA.
`We are presently conducting a phase 1/11 trial of an
`Yttrium-labeled monoclonal antibody for A1 CaP at the
`University of California Davis Cancer Center. Palliative
`responses have been observed in the first nine patients
`treated thus far.
`Novel therapeutic agents with unique mechanisms of
`action are now beginning to enter early phase clinical
`trials (7 1). These include cyclin-dependent kinase inhibi-
`tors (flavopiridol)," matrix metalloproteinase inhibitors
`(marimistat), anti-angiogenesis agents (linomide), apop-
`tosis inducers (thapsigargin), and gene therapy (autolo-
`
`* Flavopiridol is currently being evaluated in a phase I1 trial at UC
`Davis, City of Hope, University of Southern California, and The Uni-
`versity of Wisconsin.
`
`

`

`142
`
`gous or allogeneic cytokine-secreting gene-modified vac-
`cines), among others. Efforts should be directed at accru-
`ing patients into these trials.
`
`INSIGHTS
`
`Clinicians continue to have limited weapons in com-
`bating the scourge of A1 CaP. It is estimated that 107
`American men will die of the disease daily. New strate-
`gies and novel agents are necessary. Fortunately, because
`of the many advances in CaP therapeutics, we have de-
`veloped new insights into the biology and treatment of
`A1 Cap:
`1. Withdrawal of anti-androgen therapy produces
`clinical response in a proportion of patients that,
`although brief, may provide symptom relief.
`Characterization of the p53 pathway and its rela-
`tion to tumor chemosensitivity has shown that most
`clinically active drugs such as antimetabolites, to-
`poisomerase 1/11 inhibitors, and alkylating agents
`demonstrate more growth suppression in tumors
`with normal p53 status (72). Conversely, tumors
`that express a high frequency of p53 mutations
`(such as metastatic prostate cancer) are less sensi-
`tive to these “traditional” cytotoxic treatments.
`Therapies directed at overcoming the block to
`apoptosis should continue as a focus of investiga-
`tion.
`The next generation of clinical trials should not
`be futile hormonal manipulations nor repetitive
`chemotherapy. Molecular correlates should be in-
`corporated in these trials.
`Refined response criteria need to be developed,
`specially in the light of nontraditional therapies
`that are cytostatic rather than cytotoxic, with ap-
`propriate surrogate markers.
`The aggressive use of palliative care will ensure
`effective caring for patients and healing of their
`families in the absence of cure.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`ACKNOWLEDGMENT
`
`Dr. Lara is supported in part by the Veteran’s Administration of
`Northern California Health Care System.
`
`Address correspondence to: Primo N. Lara, Jr., M.D., University of
`California Davis Cancer Center, Division of Hematology-Oncology,
`4501 X Street, Sacramento, CA 95817.
`
`Lara and Meyers
`
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