ONCOLOGY. Vol. 25 No. 6

Pages: 1 2 3

REVIEW ARTICLE

Evolving Therapeutic Paradigms for Advanced Prostate Cancer

By Joshua M. Ruch, MD¹,Maha H. Hussain, MD, FACP^1,2 | May 16, 2011

¹Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan
²Department of Urology, University of Michigan, Ann Arbor, Michigan

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Abiraterone (Zytiga)
Aflibercept
AT-101
Atrasentan (Xinlay)
Bamucirumab
Bevacizumab(Drug information on bevacizumab) (Avastin)
Bicalutamide(Drug information on bicalutamide) (Casodex)
Cabazitaxel (Jevtana)
Cabozantinib
Cixutumumab
Custirsen
Dasatinib(Drug information on dasatinib) (Sprycel)
Degarelix (Firmagon)
Denosumab (XGEVA)
Docetaxel (Taxotere)
Eribulin (Halaven)
Everolimus (Afinitor)
Ipilimumab (Yervoy)
Ixabepilone
Leuprolide (Lupron)
MDV3100
Mitoxantrone(Drug information on mitoxantrone) (Novantrone)
Olaratumab
Patupilone
Ramucirumab
Sunitinib (Sutent)
Tasquinimod
Temsirolimus (Torisel)
Veliparib
Vorinostat (Zolinza)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Bone-Targeted Therapy

The development of bone metastases in prostate cancer is a complex process involving numerous proteins, growth factors, and pathways.[51] The four major players are the cancer cells, osteoblasts, osteoclasts, and mineralized bone matrix (the latter a major source of immobilized growth factors). Skeletal metastases in prostate cancer result in both osteoblastic and osteolytic lesions. Factors released by cancer cells stimulate the osteoblast to grow, differentiate, and secrete growth factors into the bony microenvironment. The enriched microenvironment in turn supports the tumor cells. On the other hand, metastatic cancer cells in the bone activate osteoclasts, leading to bone resorption. The ensuing breakdown of the bone leads to release of a variety of growth factors that stimulate osteoblastic activity; these include endothelin, insulin-like growth factor, and platelet-derived growth factor (PDGF).[51] The end result is osteoblast-mediated bone mineralization, which overcomes the osteoclast-mediated bone resorption, resulting in the formation of osteoblastic metastases. These lesions are composed of loosely packed collagen(Drug information on collagen) bundles, and in conjunction with the osteolytic activity, account for many of the skeletal complications seen in prostate cancer, including pain and fracture.[52]

Endothelin-receptor antagonists

The endothelin pathway affects cancer progression through multiple different mechanisms, including inhibition of apoptosis and promotion of angiogenesis.[53] As discussed above, the endothelin pathway appears to be highly involved in the development of bone metastasis, making it an attractive target in metastatic prostate cancer.[51]

Atrasentan (Xinlay). This was the first endothelin-A receptor antagonist to be tested in prostate cancer. Two phase III studies (one in metastatic CRPC and the other in non-metastatic CRPC) showed no significant difference in the time to progression (the primary endpoint in both studies), but statistically significant differences in PSA and bony alkaline phosphatase values were observed that favored atrasentan over placebo.[54,55] Preclinical work has suggested enhanced antitumor effects when atrasentan is combined with docetaxel.[56] A phase III Southwest Oncology Group (SWOG) Intergroup study is comparing docetaxel and prednisone(Drug information on prednisone) with atrasentan to docetaxel(Drug information on docetaxel) and prednisone without atrasentan in metastatic CRPC.[57] This trial has completed accrual and the results are expected soon.

Zibotentan. This is another endothelin-A receptor antagonist being evaluated in advanced prostate cancer. In a phase II trial, asymptomatic or mildly symptomatic patients with metastatic CRPC were randomly assigned to receive one of two doses of zibotentan or placebo.[58] The results showed no difference in time to disease progression (the primary endpoint), but overall survival was 24.5 months with the 10-mg dose of zibotentan compared with 17.3 months in the placebo group. A phase III trial evaluating this agent in patients with metastatic CRPC recently showed no improvement over placebo in overall survival.[59] Additional phase III studies are underway evaluating the efficacy of zibotentan in patients with CRPC without evidence of metastases (ENTHUSE M0) and in combination with docetaxel in patients with bone metastases (ENTHUSE M1c).[60,61]

Osteoclast (RANKL) inhibitor

The interaction between receptor activator of nuclear factor kappa B (RANK) and its associated ligand (RANKL) lead to osteoclast differentiation, activation, and survival.[51] Denosumab is a monoclonal antibody against RANKL.[62] Early studies using this agent in patients with skeletal metastases showed improvement in markers of bony turnover (urinary N-telopeptide), as well as a reduction in SREs, including pathologic fracture and spinal cord compression.

Results from a phase III study comparing denosumab and zoledronic acid(Drug information on zoledronic acid) for the prevention or delaying of SREs (defined as a pathologic fracture, radiation or surgery to bone, or spinal cord compression) in patients with CRPC and bone metastasis showed non-inferiority with denosumab, which significantly increased the time to the first on-study SRE (HR, 0.82 [95% CI, 0.71-0.95]; P = .008), with a median time of 20.7 months, compared with 17.1 months with zoledronic acid.[9] Overall survival and time to disease progression were similar in the two groups. There was a non-significant increase in the incidence of osteonecrosis of the jaw with denosumab (2.3% vs 1.3%) as well as more frequent hypocalcemia (12.8% vs 5.8%).

Currently, denosumab is FDA-approved for preventing SREs in patients with bone metastases from a variety of malignancies, including prostate cancer.[63] Although it provides another treatment option, the observed effects represent a modest clinical advantage, considering that it is no better than zoledronic acid with regard to progression-free survival or overall survival. The landscape of effective therapeutics is changing, and radiation therapy, if needed, can now be achieved with as little as one fraction.[64] The cost-effectiveness of denosumab is also a consideration when contemplating its use.

Angiogenesis Inhibition

Angiogenesis is mediated by a variety of factors, including vascular endothelial growth factor (VEGF).[65] VEGF, which is produced by both tumor cells and tumor-associated stroma in response to hypoxic conditions, binds to the VEGF receptor, leading to downstream signaling that results in new blood vessel formation.[66]

Agents targeting the VEGF pathway

Several agents targeting the VEGF pathway have been developed and are currently being investigated in clinical trials. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that targets VEGF. Promising data from phase II trials[67-69] led to a phase III study conducted by Cancer and Leukemia Group B (CALGB). This recently reported trial compared docetaxel and prednisone plus bevacizumab to docetaxel and prednisone plus placebo in men with CRPC.[70] The results showed no improvement in overall survival (the primary endpoint) as well as a significant increase in serious adverse events and treatment-related deaths with bevacizumab.

Sunitinib (Sutent) is a tyrosine kinase inhibitor that inhibits angiogenesis by targeting the VEGF and PDGF pathways. Phase II studies in CRPC have shown only modest activity for sunitinib when used as upfront therapy with docetaxel or as salvage therapy following docetaxel, and a recent phase III trial failed to demonstrate an advantage to the combination over docetaxel alone.[71,72]

The lack of a survival benefit with these two agents could be a function of the lack of efficacy of the specific agent in this disease or a reflection of the relative importance of VEGF targeting at this late stage of the disease. However, early data from other trials provide support for the potential value of targeting angiogenesis. Tasquinimod is a novel angiogenesis inhibitor that acts independently of VEGF inhibition, although its mechanism of action is unknown.[73] A randomized phase II study comparing tasquinimod to placebo in patients with metastatic CRPC showed an improvement in progression-free survival with tasquinimod (24.7 weeks vs 12.9 weeks).[74] A phase III study evaluating the effect of tasquinimod is planned.

Aflibercept (VEGF-trap) is a circulating VEGF antagonist that prevents VEGF receptor binding. Phase I studies showed activity of this agent in a variety of solid tumors.[75] An ongoing phase III study of patients with metastatic CRPC is comparing docetaxel, prednisone, and aflibercept to docetaxel, prednisone, and placebo.[76]

Cabozantinib (XL184) is an oral inhibitor of MET and VEGF receptor 2 (VEGFR2) that has demonstrated antitumor and antiangiogenic effects in preclinical models.[77] MET and VEGFR2 synergize to induce angiogenesis. Expression of MET and/or its ligand (hepatocyte growth factor [HGF]) increases with prostate cancer progression and metastasis.[78,79] Preclinical studies indicate that MET expression increases with androgen deprivation.[79,80] Upregulation of MET and the emergence of an invasive phenotype have been associated with the ability of tumors to evade antiangiogenic therapy.[81,82] A phase II trial evaluated cabozantinib in patients with a variety of cancers, including a cohort of patients with progressive CRPC who had or had not received prior docetaxel. Preliminary data reported at the recent American Society of Clinical Oncology (ASCO) genitourinary symposium indicated that cabozantinib has unique antitumor activity, as reflected by resolution of bone scans (complete or partial) in 85% of patients, reduction in bone pain, and reduction in narcotic use.[77] The overall disease control rate at 12 weeks (partial response plus stable disease) was 74%.

Other Targeted Therapies

Src/Src family kinase inhibitor

In addition to affecting prostate cancer proliferation and metastasis, Src and Src family kinases are involved in bone turnover through their induction of osteoclast activity and inhibition of osteoblast activity.[83] Dasatinib (Sprycel) is a tyrosine kinase inhibitor with activity against PDGF that has also been shown to inhibit Src and the Src family kinases.[84] In a phase II study, patients with metastatic CRPC treated with dasatinib showed evidence of disease stability and decreased markers of bone turnover.[84] A phase III study evaluating overall survival using dasatinib in combination with docetaxel in CRPC is underway.[85]

Anti-apoptosis (clusterin) inhibitor

Clusterin is stress-induced protein that in part functions as an anti-apoptotic protein.[86] It is upregulated in a variety of cancer cells, including prostate cancer, and leads to resistance to radiation therapy, chemotherapy, and hormonal therapy. Custirsen is an antisense inhibitor of clusterin. A recent phase II study randomly assigned patients with metastatic CRPC to treatment with either docetaxel and prednisone plus custirsen or docetaxel and prednisone without custirsen.[87] Although the primary endpoint of a PSA decline of more than 50% in 60% of patients was not achieved, patients who received custirsen had improvements in both progression-free survival (7.3 months [95% CI, 5.3-8.8] vs 6.1 months [95% CI, 3.7-8.6]) and overall survival (23.8 months [95% CI, 16.2-not reached] vs 16.9 months [95% CI, 12.8-25.8]). Two phase III studies evaluating the benefit of custirsen added to docetaxel retreatment as second-line therapy in CRPC and in combination with docetaxel and prednisone as first-line therapy in CRPC are ongoing.[88,89]

Conclusion

Prostate cancer is a heterogeneous disease marked by a complex molecular profile. The identification and elucidation of numerous signaling pathways involved in disease progression and treatment resistance has paved the way for the development of new therapeutic agents, some of which are now available for clinical use. With the advent of these new drugs comes the opportunity for more personalization of therapy, thus enhancing the benefit-to-risk ratio and cost-effectiveness of treatment. Now that it has been demonstrated that survival can be improved with a diverse group of agents, further advances will rely on ongoing improvements in the understanding of prostate cancer biology, along with prompt, rigorous testing of promising agents in well-designed and well-conducted trials.

Financial Disclosure: Dr. Ruch has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Hussain serves as a consultant to Bristol-Myers Squibb, Merck, and Lilly/Imclone (in areas unrelated to the subject matter of this paper), and she has received an honorarium from Ferring Pharmaceuticals (also for work in areas unrelated to the subject matter of this paper).

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by Steven Porsche | December 30, 2011 10:33 AM EST

Dr Hussain should also note that the FDA is well aware of this class of therapies' delayed effect on progression:

"Testing cancer vaccines using the conventional model may not allow time for development of an anti-tumor immune response needed for activity/effectiveness because of the potentially short time interval from administration of study agent to subsequent disease progression in patients with metastatic cancer....

In oncologic practice, patients are usually taken off current treatment when they have disease progression/recurrence. Because cancer vaccines need time to elicit an immune response that could manifest as biological activity (i.e., a tumor specific immune response), a delayed effect can be expected in the subjects who have received the vaccines. Shortly after the initial cancer vaccine administration, subjects may experience disease progression prior to the onset of biological activities or effects from the vaccine (delayed effects)."

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm182443.htm

by robert rostock | December 30, 2011 10:29 AM EST

I don't understand the reasoning for including an active agent as a control against future trials of an agent that already is known to improve survival. . What does lack of effect on progression have to do with requiring provenge be tested against an active agent as a control? That doesn't solve the problem of figuring out who benefits. We still won't know who benefited from provenge even if it is tested against an active agent. Survival is still the gold standard. Provenge affects that. Also, taxotere patients with visceral mets were a minority, so what? Provenge isn't approved for visceral mets. With other approved agents now on board, its logical that any new treatment will have to be tested against proven therapies before they are approved for anything but end of the line treatment.
To carry the author's logic to its conclusion., survival is the gold standard. So any new treatment should be tested with provenge as a control not visa versa. Provenge has already met the gold standard of approval by affecting survival..
I addition we never know if a treatment will lbenefit a patient before we try it. It is only in retrospect that we know an agent like taxotere benefited a patient. All patients still receive the treatment just like they would with provenge. The issue for provenge becomes one of when to add another treatment or sequencing since there is no surrogate marker for survival. Sequencing trials need to be performed not trials comparing provenge with active controls. We already know provenge affects survival.

by Steven Porsche | December 30, 2011 10:09 AM EST

Dr Hussain writes the following critigue of Provenge: "As in the other two studies, no antitumor effect was seen, as reflected by the lack of difference in time to disease progression, symptom improvement, decrease in PSA level, or other measure of disease response.

The most common adverse reaction seen with sipuleucel-T was an infusion reaction, occurring within 24 hours in 71.2% of patients (3.5% had grade 3 reactions) and manifested by chills, fever, fatigue, nausea, tachycardia, and hypertension.[19-21] Other common side effects included headache, back pain, and joint pain. Overall, grade 3 or 4 adverse events occurred in 23.6% and 4% of patients, respectively, with the most common being back pain and chills.[7] In one trial, cerebrovascular events occurred in 7.5% of patients treated with sipuleucel-T (11 of 147) vs 2.6% of patients in the control group (2 of 76).[21]

A common concern regarding sipuleucel-T has been the lack of any demonstrable antitumor effect in any of the randomized trials as compared with results in the control groups-and therefore, the inability to assess response at the individual patient level.[22,23] It remains to be proven whether conventional response measures are appropriate with this class of agents or not. If not, then until adequate efficacy assessment measures are established, we strongly recommend that future phase III testing of such agents include an active control arm proven to be of benefit so as to allow confidence in the trial results with regard to comparable or superior outcome. This is especially important considering the per-patient cost of treatment with sipuleucel-T and the fact that it does not obviate the need for chemotherapy.[23] Proponents of this agent argue that the cost is comparable to that of other biologic agents approved by the FDA and that the price may be offset by the more favorable side-effect profile of sipuleucel-T (compared to chemotherapy).[24] However, since this agent was tested in a different patient population than that included in the docetaxel trials (which allowed accrual of patients with pain and visceral disease), and since none of the trials compared sipuleucel-T to an active control with established clinical benefit, the fact remains that thousands of patients will receive a full course of therapy without the certainty of knowing who may be benefiting."

Dr. Hussain makes some clear factual errors in her critique of Provenge.

Dr. Hussain cites above:

" In one trial, cerebrovascular events occurred in 7.5% of patients treated with sipuleucel-T (11 of 147) vs 2.6% of patients in the control group (2 of 76).[21]"

What citation 21 actually says:

"Cerebrovascular events were reported for 8 of 338 patients (2.4%) in the sipuleucel-T group and 3 of 168 patients (1.8%) in the placebo group (P=1.00 by Fisher's exact test). The incidence rate was 1.33 cerebrovascular events per 100 person-years (95% CI, 0.58 to 2.62) in the sipuleucel-T group and 1.11 per 100 person-years (95% CI, 0.23 to 3.24) in the placebo group. The median interval between the most recent infusion and the event was 210 days in the sipuleucel-T group and 196 days in the placebo group."

http://www.nejm.org/doi/full/10.1056/NEJMoa1001294#t=articleTop

What Dr. Hussain cites above:

"The most common adverse reaction seen with sipuleucel-T was an infusion reaction, occurring within 24 hours in 71.2% of patients (3.5% had grade 3 reactions) and manifested by chills, fever, fatigue, nausea, tachycardia, and hypertension.[19-21] Other common side effects included headache, back pain, and joint pain. Overall, grade 3 or 4 adverse events occurred in 23.6% and 4% of patients, respectively, with the most common being back pain and chills.[7]"

What Dr. Hussain left out on citation 7:

"Serious adverse events (SAEs) include any life-threatening or fatal event, inpatient hospitalization, or persistent or significant disability. Overall, 24.0% of subjects in the sipuleucel-T group and 25.1% of subjects in the placebo group developed an SAE."

http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM213114.pdf

Then Dr. Huissain cites Dr. Longo's in error cost analysis which was corrected below by Dr. Nabhan:

"In his editorial on the efficacy of sipuleucel-T in castration-resistant prostate cancer, Longo argues that the cost of this immunotherapy is high per life saved, and he questions the overall survival advantage without a measurable antitumor effect.1 First, Longo suggests that $1,800 per month is sufficient to care for patients with castration-resistant prostate cancer; this estimate was based on retrospective registry data, which included patients who did not receive docetaxel.2 According to the Centers for Medicare and Medicaid Services, the cost per cycle of docetaxel is $2,413 (based on 1.8% of body-surface area and a docetaxel dose of 75 mg per square meter).3 The cost for a median of 10 cycles4 is $24,000 per patient. This cost is independent of treatment-related supportive measures, blood transfusions, emergency room visits, and hospitalizations, which can easily double the cost of a complete course of chemotherapy, based on very conservative payment rates in the United Kingdom.5 Second, overall survival was superior with sipuleucel-T, despite a crossover trial design. The lack of effect on time to progression may be explained by frequent monitoring that can detect disease progression before the onset of antitumor activity. The fact that other immunotherapy studies showed an overall survival advantage without affecting time to progression6 supports this hypothesis and suggests a class effect."

Chadi Nabhan, M.D.

http://www.nejm.org/doi/full/10.1056/NEJMoa1001294#t=letters

Nor does Dr. Hussain address the cost of Zytiga at $5k/mo. which could get very costly if used pre-chemo, ie, possibly over 20 plus months, nor the health effects of long term steroid usage, nor all the patient monitoring required for Zytiga, ie, electrolytes, liver function, etc.

This article reviewed

Advanced Prostate Cancer: New Agents, New Questions

Evolving Therapeutic Paradigms for Advanced Prostate Cancer: What's Needed to Make Optimal Use of the New Treatments

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