A Renaissance in the Medical Treatment of Advanced Prostate Cancer

Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.

Introduction

Treatment of metastatic, hormone-refractory prostate cancer has posed a significant challenge for urologists and oncologists given the paucity of available treatments in this setting. Prior to the early 2000s, mitoxantrone was considered approved for use in prostate cancer on the basis of improved quality of life measures in men with progression of disease in spite of castrate levels of androgens which drive prostate cancer growth. Docetaxel later displaced mitoxantrone as the first-line chemotherapy of choice, offering increased overall survival by a few months and additional palliative benefits over mitoxantrone. Other therapies have also been described, but without a clear survival advantage, leaving clinicians with few other effective medical options for advanced disease. In the last decade, however, a renaissance in our understanding of the molecular mechanisms associated with castration-resistant prostate cancer (CRPC) has led to the emergence of several new treatment options for men with advanced prostate cancer, ranging from immunotherapies to a new generation of androgen receptor (AR)-targeted therapies. This review will examine five emerging therapies for CRPC, detailing the molecular basis for their activity and describing the clinical trials supporting their potential use in this setting.

Immunotherapies

Sipuleucel-T (APC8015)

In the late 1990s, researchers began to investigate the concept of tumor-specific immunity, whereby an immune response is stimulated in order to target tumor cells for destruction.[1] This idea was applied to the development of sipuleucel-T (Provenge). In the course of treatment with Provenge, the patient’s antigen-presenting cells (APCs, specifically dendritic cells) are collected via leukapheresis and then loaded ex-vivo with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). After culturing this fusion protein with the dendritic cells, the product is then re-infused into the patient, activating T-cells via class I and class II HLA molecules and resulting in a beneficial immune response against PAP.

In a phase I-II trial, 31 patients were treated with sipuleucel-T.[2] The phase I portion examined patient response to dose escalation in three tiers of patients with metastatic CRPC, all of whom had undergone androgen deprivation with androgen blockade and subsequent antiandrogen withdrawal. The most common adverse reactions were fever, myalgia, and mild urinary complaints. Only three patients were noted to have had a prostate-specific antigen (PSA) decline of ≥ 50% from baseline, despite all patients exhibiting a measurable immune response to the fusion protein and 38% developing an immune response specific to PAP. While some patients demonstrated a clear clinical response in the form of a significant drop in PSA, the authors noted that PSA may not be a valid indicator of meaningful anticancer activity for immune-based therapies as future trials would eventually demonstrate.

A second phase II trial of sipuleucel-T in 21 patients with metastatic CRPC was conducted and resulted in a similar overall lack of effect on PSA levels. However, one patient exhibited a potent, durable biochemical response, with PSA falling from 221 ng/mL to undetectable and sustaining these levels for more than four years.[3] To address the potential inadequacy of PSA as a measure of meaningful clinical activity, investigators altered the definition of “progression” from a biochemical change (in PSA level), to objective enlargement of soft tissue disease or the appearance of two or more new lesions on radionuclide bone scan. Using this new definition, median time to progression was 118 days.

A phase III trial enrolled 127 asymptomatic men with metastatic CRPC randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The trial was designed to measure a primary outcome of time to progression (defined as pathologic fracture, spinal cord compression, new-onset pain associated with metastasis, two or more lesions on bone scan, or > 50% increase in measurable cancer burden).[4] Overall, there was no significant difference in time to progression between the two treatment arms, but there was a 4.5 month improvement (P = .01) in overall survival in the sipuleucel-T arm. However, because this study was not originally designed to detect an increase in overall survival, more evidence was requested to support its use in men with CRPC when initially evaluated by the FDA for approval in 2007.

To bolster proof of clinical efficacy, investigators proceeded with a second phase III, double-blind, placebo-controlled, multicenter trial of sipuleucel-T that was designed to measure its effect on overall survival, and the results were published in July 2010.[5] In this trial, 512 patients were randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The study detected a 4.1-month improvement in overall survival over placebo, despite allowing 109 of 171 patients in the placebo group to cross over and receive salvage sipuleucel-T (prepared and cryopreserved at the time of placebo preparation). Adverse events in the treated group were primarily limited to fever, chills, and headache at or near the time of the infusion. Similar to previous studies, there were no differences in the time to disease progression (measured radiographically at 6, 14, 26, 34 weeks and every 12 weeks thereafter) between the two groups.

Investigators attributed the discordance between the observed survival benefit and the lack of effect on disease progression to a possible class effect, as a similar phenomenon has been reported in a study on poxviral-based PSA-targeted immunotherapy (PROSTVAC-VF).[6] Similarly, other studies of metastatic CRPC have shown a lack of correlation between disease progression and overall survival.[4,7] Sipuleucel-T was approved by the FDA in April of 2010 for the treatment of metastatic CRPC which is asymptomatic or minimally symptomatic.

Denosomab

The use of androgen-deprivation therapy (ADT), either medically or surgically, is associated with clear metabolic changes, including a decrease in bone mineral density (BMD).[8,9] Because prostate cancer also frequently metastasizes to the bone, a second skeletal insult is often added to those with advanced disease on ADT. Zoledronic acid (Zometa) is a potent bisphosphonate that has been approved for use in men with metastatic CRPC. Its role was established by a study of men with metastatic CRPC by Saad et al, in which 4 mg of zoledronic acid was given every three weeks and reduced the incidence of skeletal related events (SRE) from 44% in the placebo arm to 33% in the zoledronic acid arm.[10] SREs were defined as a pathologic fracture, spinal cord compression, orthopedic interventions, radiation therapy to the bone, or a change in antineoplastic therapy to treat bone pain. Other dosing schedules of zoledronic acid have been studied in phase II studies assessing BMD, showing that zoledronic acid administered every three months or even annually may effectively preserve BMD in those treated with ADT, although these studies were not designed to assess for changes in SRE rates. One small study has examined the oral bisphosphonate alendronate (fosamax) and found that it also appears to maintain BMD in men treated with ADT for prostate cancer.[11]

The primary action of bisphosphates in improving bone health in those with osteoporosis is via a reduction in bone resorption, likely via inhibition of osteoclast activity. With ADT, the normal balance between osteoclast and osteoblast activity is altered, leading to bone loss or frank osteoporosis. Osteoclasts therefore play a primary role in bone resorption and are mediated via receptor activator of nuclear factor-κβ (RANK) ligand, which directly stimulates their action. Denosumab (Prolia) is a recently introduced, fully human monoclonal antibody against RANK ligand; denosumab is effective in osteoclastic bone resorption.

Denosumab has been tested in several clinical settings of BMD loss, including in groups of post-menopausal women and men wi;th CRPC. Denosumab is now FDA-approved for the treatment of post-menopausal bone loss in women at high risk for fracture.[12] With regard to prostate cancer, one study tested denosumab in cancer patients with bone metastases (45% of whom had prostate cancer) and found persistently elevated levels of the bone turnover marker N-telopeptide in the urine, despite the use of intravenous bisphosphonates.[13] Notably, the levels of N-telopeptide were successfully suppressed by denosumab in two-thirds of patients, suggesting that denosumab was more effective at suppressing osteoclast activity than were bisphosphonates. In a phase III study of men with non-metastatic CRPC, denosumab increased the lumbar spine BMD by 5.6%, while the placebo arm averaged a 1% loss in BMD. From a clinical outcomes standpoint, a reduction in the incidence of new vertebral fractures was also noted with denosumab, suggesting a primary preventative role in this setting.[14] In a separate randomized, phase III study of denosuamb versus zoledronic acid in patients with metastatic CRPC, denosumab significantly improved the median time to first SRE (20.7 versus 17.1 months) compared to zoledronic acid.[15]

From the published literature, denosumab appears to be well tolerated, however, denosumab is associated with osteonecrosis of the jaw (ONJ), as is high-potency bisphosphonate therapy (by virtue of the osteoclastic inhibition). In a recent report of metastatic CRPC patients, 2.3% of the denosumab-treated patients developed ONJ, versus 1.3% in the zoledronic acid arm (P = .09), and hypocalcemia was observed more commonly with denosumab than with zoledronic acid (13% versus 6%).[15] Since denosumab is a monoclonal antibody, less renal toxicity is expected with this drug, in comparison to high potency bisphosphonates.

In summary, denosumab is a new monoclonal antibody directed against RANK ligand and is a potent inhibitor of osteoclast activity. It is currently approved for the treatment of osteoporosis in high-risk post-menopausal woman. Published data regarding its use in metastatic CRPC show a delay in the time to first SRE compared to zoledronic acid treatment. Osteonecrosis of the jaw will likely be observed with denosumab in a similar pattern to zoledronic acid, although denosumab use is expected to be associated with fewer cases of renal toxicity.

Antiandrogens

Abiraterone acetate

This compound, first described in 1995, is an orally-available, highly selective, irreversible inhibitor of the CYP17A enzyme, which is responsible for 17α-hydroxylase and c17,20-lyase activity in steroidogenesis (Figure 1). The inhibition of the CYP17A enzyme results in the suppression of serum androgens derived from adrenal and testicular sources.[16,17] Castration through androgen deprivation therapy (ADT)-namely treatment with leutenizing-hormone releasing hormone (LHRH) agonists and newer antagonists-primarily affects the gonadal, but not the extra-gonadal production of androgens from the adrenal glands and from intratumoral sources. The antifungal ketoconazole acts through a mechanism similar to abiraterone acetate, however its activity is non-specific and associated with a number of adverse effects, which limits its durability and efficacy.[18-20] Ketoconazole’s antitumor activity in patients with CRPC, however, supports the rationale for pursuing a more targeted, specific agent against the extra-gonadal production of testosterone.

The initial phase I trial of abiraterone acetate examined its safety and tolerability in 21 patients. Eligibility criteria included good performance status (Eastern Cooperative Oncology Group performance status 0-1); progressive disease (radiographic enlargement or increasing serum PSA); no prior chemotherapy or radionuclide treatment; and castrate levels of testosterone (< 50 ng/dL). For patients with PSA progression during the study period, investigators allowed for the addition of dexamethasone as salvage therapy to modulate adrenocorticotropic hormone (ACTH) production. ACTH is up-regulated in response to low levels of cortisol induced by abiraterone acetate.[17] The primary toxicities reported were related to secondary mineralocorticoid excess, presenting as hypertension, hypokalemia and peripheral edema. These were treated with a potassium-sparing aldosterone receptor antagonist or escalation to dexamethasone if needed (occurred in two patients). With a plateau effect noted at doses above 750 mg daily, the recommended phase II dosing was designated as 1000 mg daily. Patients with progression (indicated by rising PSA) were noted to have no increase in androgenic compounds downstream of CYP17, indicating that resistance most likely occurs through some other mechanism.

An early, 54-person phase II study of abiraterone acetate was designed to examine its effect in chemotherapy-nave CRPC patients.[21] This study’s primary end point was a ≥ 50% reduction in PSA any time after 12 weeks of entering the trial, confirmed four weeks later by a follow-up PSA test. Other secondary end points were also defined, including radiological assessment of soft tissue tumors using Response Evaluation Criteria in Solid Tumors (RECIST) criteria [22] and circulating tumor cell (CTC) counts. Circulating tumor cell counts have previously been shown to correlate to survival.[23,24] Specifically, CRPC patients with an unfavorable CTC level (≥ 5 per 7.5 mL blood) have exhibited decreased overall survival (11.5 versus 21.7 months) compared to those with favorable levels (<5 per 7.5 mL of blood). Furthermore, if a patient transitions from an unfavorable to favorable CTC level with treatment, they assume the good prognosis observed in the favorable CTC group. Given the difficulty of using PSA as a survival surrogate, some researchers have advocated use of CTC counts as a clinical marker instead.

The results of this trial of 54 chemotherapy-nave CRPC patients treated with abiraterone acetate showed that 28 of 42 of patients (67%) had PSA declines of ≥ 50%.[21] Additionally, nine of 24 patients (38%) with soft tissue masses were found to have partial responses by RECIST criteria, and 10 of 17 patients (59%) went from an unfavorable CTC level at baseline to a favorable CTC level with treatment. Secondary mineralocorticoid excess (presenting as hypokalemia [88%], hypertension [40%], and peripheral edema [31%]) was the primary side effect noted. Three patients required dexamethasone for symptomatic fluid overload. The median time to PSA progression was 229 days.

Interestingly, 39 of these 54 patients eventually received dexamethasone in response to PSA progression (after initial treatment with single-agent abiraterone acetate), and 33% of this group of patients experienced a secondary PSA decline of ≥ 50%. The authors hypothesize that this may be related to upstream steroidal precursors activating androgen receptor (AR), and that the addition of dexamethasone suppresses central ACTH that would otherwise enhance the synthesis of upstream steroidal compounds.

Phase II results from testing abiraterone acetate (1,000 mg daily) with and without prednisone (5 mg twice daily) in patients who failed cytotoxic therapy were reported at the beginning of 2010.[25,26] The first study of abiraterone acetate plus prednisone revealed PSA declines of ≥ 50% from baseline in 22 of 58 patients (36%); soft tissue tumor partial responses in 4 of 22 patients (18%) and CTC conversions from unfavorable to favorable counts in 10 of 29 patients (34%). Notably, 47% of patients in this study had received prior ketoconazole therapy, which may confer some resistance and account for the decreased effect reported in this population. The overall median time to PSA progression was 169 days, but when accounting for prior ketoconazole exposure, nave versus ketoconazole-treated patients had a median time to progression of 198 versus 99 days, although this difference was not significant. Profiles from earlier studies showed similar side effects, and no grade 4 adverse events were seen. The incidences of symptoms from secondary mineralocorticoid excess were reduced with the concomitant use of low-dose prednisone-only 5%, < 5% and < 10% were reported to have hypokalemia, hypertension or edema during the study period, respectively.

The primary and secondary outcomes of the phase II study without prednisone in docetaxel-treated patients (n = 47) were nearly identical, but with 55%, 17% and 15% experiencing hypokalemia, hypertension or edema, suggesting that low-dose corticosteroid should be used in this population to mitigate these side effects.[26] Some debate exists, however, over the use of prednisone in chemotherapy-nave patients who are otherwise asymptomatic and could potentially be treated with an aldosterone receptor antagonist. Attard et al have suggested that a randomized trial in asymptomatic, pre-docetaxel patients be conducted to compare concomitant use of low-dose corticosteroids with abiraterone acetate to abiraterone acetate alone, with addition of low-dose corticosteroids only when disease progression is identified.[27]

A randomized, multicenter phase III trial of abiraterone acetate plus prednisone against placebo plus prednisone in CRPC patients who failed docetaxel therapy is now completely accrued, though the final results are not yet available.[28] A second phase III trial of abiraterone acetate in metastatic, chemotherapy-nave, CRPC was also recently fully accrued.[29] Given the suggestion that prior ketoconazole exposure may reduce the efficacy of abiraterone acetate, a dedicated study of this phenomenon was performed and reported in 2010. Results showed that 47% of those with prior ketoconazole treatment versus 64% without prior exposure experienced a PSA decline of ≥ 50%.[30] Further study of the presumed resistance conferred by ketoconazole in patients treated with abiraterone acetate is planned. For now, prior treatment with ketoconazole constitutes one of the exclusion criterion in ongoing phase III studies.

MDV3100

This experimental compound, a non-steroidal, second-generation antiandrogen, has been shown to be a highly potent antagonist of AR, with an affinity for AR that is five times greater than the affinity of bicalutamide for AR.[31] While other drugs in this class have some measurable agonist activity, MDV3100 is unique in that it exhibits no such activity, reduces nuclear translocation of AR, and blocks binding of the receptor to DNA androgen response elements.[32] Initial characterization of MDV3100 showed a five-fold reduction of nuclear versus cytoplasmic AR concentrations when compared to bicalutamide. Given that the development of CRPC involves cellular changes that include up-regulation of ARs in the setting of LHRH agonist or antagonist therapy, MDV3100 could potentially be used in combination with ADT, taking advantage of their different mechanisms of action in targeting AR. Several studies have demonstrated persistent intratumoral androgen synthesis despite central suppression of the hypothalamus-pituitary-adrenal axis, and the effect of this local production may be effectively blocked by MDV3100.[33,34]

In a phase I-II study of MDV3100 involving 140 men with CRPC (of whom 75 failed taxane-based therapy), a 50% reduction in PSA was noted in 62% of chemotherapy-nave patients and 51% of post-chemotherapy patients.[35] The median time to PSA progression was 41 weeks for chemotherapy-nave patients and 21 weeks for patients with prior cytotoxic therapy. Additionally, 22% of patients with measurable disease (13 of 59 patients) responded by RECIST criteria and 56% of bone lesions were stabilized. The most commonly observed adverse event was fatigue (in 12 patients), and seizures were observed in two patients who were at doses of 360 and 600 mg daily. Subsequent doses were reduced to 240 mg daily, and most patients were found to tolerate this regimen.

The effect of MDV3100 on CTCs has also been examined. Of patients in the phase I/II trial with an unfavorable baseline CTC count, 49% converted to favorable counts, including 75% of chemo-nave and 37% of the post-chemo patients. Additionally, 76% of those with a favorable CTC conversion had a PSA decrease of 50% or more.

MDV3100 is currently being evaluated in a multicenter phase III randomized trial (AFFIRM trial) which is evaluating MDV3100 versus placebo in men with CRPC who failed prior docetaxel therapy with a primary endpoint of overall survival.[36]

Cytotoxics

Cabazitaxel

The development and use of cytotoxic chemotherapy for the treatment of prostate cancer has lagged behind the use of this type of therapy in other common epithelial cancers. In the 1990s, mitoxantrone in combination with prednisone was approved for the treatment of advanced prostate cancer, based on improvement in palliative and quality of life measures.[37] In 2004, docetaxel was reported to yield an improvement in survival when compared to mitoxantrone, in men with advanced CRPC.[38] Tannock et al compared docetaxel and prednisone, given every one or every three weeks, to mitoxantrone and prednisone administered every three weeks.[39] This study showed a statistically significant improvement in survival (of approximately three months) with mature follow-up data comparing mitoxantrone to docetaxel given every three weeks.[40] On this basis, docetaxel chemotherapy has become the standard first-line chemotherapy treatment for advanced CRPC.

Since the approval of docetaxel, there has been no clear standard of care in the second-line chemotherapy setting. Mitoxantrone has been used, but its activity after docetaxel progression is modest.[41] Cabazitaxel (Jevtana), a microtubule inhibitor with a mechanism of action that is similar to docetaxel, was approved by the FDA in June of 2010 for the treatment of metastatic CRPC after the use of docetaxel chemotherapy.[42] In a recently reported, randomized, phase III trial, cabazitaxel given every three weeks with prednisone improved the median overall survival by 2.4 months (15.1 versus 12.7 months), when compared to mitoxantrone and prednisone.[43] Overall, this therapy was well tolerated, with a median of six cycles of cabazitaxel versus four cycles of mitoxantrone administered to study participants, respectively. Notably, bone marrow suppression was observed in those treated with cabazitaxel, with a 7.5% incidence of febrile neutropenia versus 1.3% in the mitoxantrone arm. Based on its mechanism of action on the microtubules, special attention was paid to cumulative neurotoxicity, but this was not commonly observed as a severe (grade 3-4) adverse event, despite previous docetaxel treatment in all of these patients. In summary, cabazitaxel is now established as a standard of care treatment for prostate cancer patients fit for second-line treatment after docetaxel chemotherapy. The main serious toxicity is bone marrow suppression, which may be minimized by granulocyte-colony stimulating factor (G-CSF) support.

Future Directions

We have presented five newly

emerging medical therapies for patients with CRPC that will substantially increase our treatment options in this setting. Investigators continue to explore other molecular targets both in the immune system and in prostate cancer cells themselves. For example, CTLA-4, an immunomodulatory molecule that down-regulates T-cell function can be antagonized via a humanized monoclonal antibody to stimulate an antitumor immune response.[44] PROSTVAC-VF, a recombinant poxviral vector, has also been shown to stimulate a T-cell response against prostate cancer cells:[45] phase III trials are currently underway. Additionally, cytotoxic therapy using a class of molecules called epothilones, which are non-taxane microtubule destabilizers, is currently being explored[41], and anti-VEGF, anti-angiogensis agents, endothelin receptor antagonists, antisense oligonucleotides, and histone deacetylase inhibitors are also considered potential targets, and are each in various phases of study.

Conclusion

For many years, the only treatment that showed a true survival advantage for CRPC was docetaxel chemotherapy. However, as we have described here, sipuleucel-T and cabazitaxel have been approved by the FDA and offer an improvement in overall survival when used in this setting. Several other agents, including abiraterone acetate, MDV3100, and denosumab are in the late stages of clinical development for men with CRPC, and these new treatments represent a dramatic period of therapeutic advancement in the field of urologic oncology, and promise a much-improved therapeutic armamentarium for the treatment of CRPC.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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