Advanced Prostate Cancer: New Agents, New Questions

Drs. Ruch and Hussain provide an excellent overview of the emerging therapeutic agents and targets for advanced prostate cancer. With the recent increase in effective treatments, one can only hope that the therapeutic nihilism that has plagued this disease will continue to give way to exuberant research efforts, especially since the new agents highlight several important questions that are in need of attention.

Advances in prostate cancer therapy have been hampered by the absence of molecular sub-characterization. Whereas in breast cancer not all tumors express hormone receptors, and expression is strongly linked to response, essentially all prostate tumors express the androgen receptor and will respond to androgen-targeted therapy, at least initially. Thus, all prostate cancers get the same first-line treatment, although we know their behavior can be vastly different. There has not yet been a consistent molecular explanation of why the time to development of castration resistance is so variable, nor have any predictors been validated to facilitate decision-making at the time of castration resistance, when either chemotherapy or a tertiary hormone manipulation may be employed. The ability to predict which patients will have a sub-optimal response to androgen deprivation would facilitate study of new treatment approaches, including combined blockade as opposed to monotherapy, up-front chemohormonal therapy, or earlier incorporation of new agents. Another issue, how best to sequence chemotherapy for castration-resistant disease, will become more complicated as the new androgen-targeted therapies mentioned by the authors come into commercial availability. Clinical trials could be designed to answer specific questions (for instance, is there a survival difference between men who are randomly assigned to treatment with abiraterone after progression on standard androgen deprivation and those assigned to treatment with docetaxel [Taxotere]?). However, accrual to such trials could suffer from patients’ and physicians’ preconceptions regarding the correct approach. Having a biologic basis for identifying individuals who will be sensitive to continued targeting of androgen synthesis and/or the androgen receptor (AR) will become critical in designing trials capable of answering these important questions efficiently. These questions will not be answered simply with the results from randomized phase III trials comparing a given new agent (abiraterone, MDV3100, etc) to placebo prior to docetaxel-unless perhaps the molecular correlates built into the trial are successful at identifying individuals who are “rapid progressors” or “big responders” to the new therapy.

Also in need of further attention is the question of how to optimize quality of life for our prostate cancer patients. With their relatively long survival even in the face of advanced disease, and variable development of pain for men with bony metastasis, oncologists must weigh treatment-related adverse effects against the potential for improved survival, especially in men without cancer symptoms. Quality of life may drive patients’ decision to pursue sipuleucel-T (Provenge) therapy instead of docetaxel, given that it has few side effects and a short treatment course. However, as the authors point out, sipuleucel-T does not delay disease progression and there are few objective responses. Thus for men with symptomatic disease, chemotherapy, with its proven track record in palliating cancer symptoms[1] and favorable overall effect on quality of life, would be preferred. Formal assessment of quality of life should be a part of all future comparative trials, so that we will be better equipped to counsel our patients as the therapeutic opportunities increase.

The final and perhaps most revolutionary paradigm shift that must occur as a result of the evolution of the therapeutic landscape in prostate cancer, centers on the question of how to measure response, and what the relationship is between response and clinical benefit. Sipuleucel-T is an important example, with a significant overall survival advantage despite lack of tumor response or delayed time to disease progression. Other new agents may also yield patterns of response that are not straightforward. While changes in PSA level during treatment, both reductions and elevations, have been correlated with survival in various published trials,[2,3] it remains somewhat controversial whether therapy should be changed on the basis of PSA level alone.[4,5] Indeed, an initial elevation in PSA level can be followed by response during chemotherapy.[6] In addition, there is cross-talk between the AR and PSA genes, such that therapies could increase AR-related expression of PSA while inducing cell death, making PSA elevation an unreliable marker.[7] As a real-world example, the authors mention that the phase III studies of atrasentan failed to find a difference in time to disease progression with atrasentan; however, further analysis revealed that subgroups experienced clinical benefit,[8] and it was hypothesized that a stronger efficacy signal might have been evident if men had not discontinued treatment early, simply because of a rising PSA level. To further complicate matters, there is a newly recognized “flare” phenomenon, described in the clinical trials of abiraterone, in which the presence of a new area of tracer uptake on the first bone scan was not necessarily predictive of progression on a repeat scan, but could be associated with response [9]. Newer trial designs allow patients to continue receiving treatment despite rising PSA levels, and the approach to interpretation of imaging response is also being revised. It appears that, especially with the emerging therapies for advanced prostate cancer, oncologists will be called on to further reassure patients that their therapy may still be successful, despite PSA or bone scan changes that would previously have been taken as evidence to the contrary. Our reassurance will be critical to ensuring that our patients have the opportunity to benefit from the new therapies.

Financial Disclosure: Dr. Dorff has been a consultant for Ortho Biotech and Dendreon and serves on the speakers bureau for Dendreon. Dr. Pinski has received research support from sanofi-aventis; he has been a consultant for sanofi-aventis, Centocor, Novartis, and Genentech; and he has served on speakers bureaus for sanofi-aventis, Centocor, Novartis, and Amgen.

References:

References:

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2. Small EJ, McMillan A, Meyer M, et al. Serum prostate-specific antigen

decline as a marker of clinical outcome in hormone-refractory prostate cancer patients: association with progression free survival, pain end points, and survival. J Clin Oncol. 2001;19:1304-11.

3. Hussain M, Goldman B, Tangen C, et al. Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group trial 9346 (intergroup study 0162) and 9916. J Clin Oncol. 2009;27:2450-6.

4. Collette L, Burzykowski T, Carroll KJ, et al. Is prostate-specific antigen a valid surrogate endpoint for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organization for Research and Treatment of Cancer, the Limburgs Universitaire Centrum, and AstraZeneca pharmaceuticals. J Clin Oncol. 2005;23:6139-48.

5. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 2008;26:1148-59.

6. Berthold DR, Pond GR, Roessner M, et al. Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life response and survival in the TAX327 study. Clin Cancer Res. 2008;14:2763.

7. Jia L, Coetzee GA. Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. Cancer Res. 2005;65:8003.

8. Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol. 2003;21:679-89.

9. Shah SK, Ryan CJ, Kilian C, et al. Bone scan “flare” in patients receiving abiraterone acetate for metastatic castration resistant prostate cancer: analysis of data from a phase II study of the Department of Defense prostate cancer clinical trials consortium. J Clin Oncol 2010;28(suppl):abstr 4545.