Update Drug and Device Development for Localized Prostate Cancer Report of a Food and Drug Administration/American Urological Association Public Workshop Jonathan P. Jarow, Ian M. Thompson, Paul G. Kluetz, John Baxley, Rajeshwari Sridhara, Peter Scardino, Peter Carroll, Peter Albertsen, H. Balentine Carter, Otis Brawley, Oliver Sartor, Howard Sandler, James J. Kiefert, and Ronald A. Morton Jr Summary of the discussion at a public workshop cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association reviewing potential trial designs for product and device development for the treatment of localized prostate cancer. Product development for treatment of localized prostate cancer has been stymied by the impracticality of using overall survival as an endpoint in patients with localized disease and the lack of acceptable surrogate endpoints. A workshop evaluating potential trial designs for the development of therapies for localized prostate cancer was held in San Diego, CA, in May 2013. Invited experts represented multiple stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates. The expert panel discussed development of products for all risk strata of clinically localized prostate cancer. The panel responded to specific questions from FDA, discussing trial design for patients with low-, intermediate-, and high-risk prostate cancer, focal therapy for prostate cancer, patients who have undergone definitive radiation therapy, and adjuvant therapy for patients undergoing radiation therapy or surgery. Expert commentary provided by the panel will inform a planned FDA guidance on pathways for product and device development for treatment of localized prostate cancer and will be discussed at meetings of the FDA’s Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products or devices for the treatment of this disease. UROLOGY 83: 975e979, 2014. Published by Elsevier Inc.
T
he U.S. Food and Drug Administration (FDA) has partnered with the American Urological Association to hold public workshops evaluating potential trial designs for product development (drugs, biologics, and devices) for the treatment of localized genitourinary cancers. These workshops are designed to engage key opinion leaders and stakeholders who understand the unique problems associated with trial
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, MD; the Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX; the Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD; the Division of Biometrics V, Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD; the Department of Surgery, David H. Koch Chair, Memorial Sloan-Kettering Cancer Center, New York, NY; the Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; the University of Connecticut Health Center, Farmington, CT; Johns Hopkins School of Medicine, Baltimore, MD; the American Cancer Society, Emory University, Atlanta, GA; Laborde Professor for Cancer Research, Departments of Medicine and Urology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA; Ronald H. Bloom Chair in Cancer Therapeutics, Department of Radiation Oncology, CedarsSinai Medical Center, Los Angeles, CA; Board Chairman Emeritus, Us TOO, International, Des Plaines, IL; and the American Medical Systems, Minnetonka, MN Reprint requests: Jonathan P. Jarow, M.D., Office of Hematology and Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993. E-mail: [email protected] Submitted: October 18, 2013, accepted (with revisions): October 20, 2013
Published by Elsevier Inc.
design and product development for these diseases. Issues highlighted at these workshops will be brought to the Oncologic Drugs Advisory Committee (ODAC), FDA’s statutory advisory body for review of oncology drugs. Discussions at both the workshops and ODAC will inform guidance that FDA is preparing on clinical trial design for localized prostate cancer product approvals. A workshop on localized prostate cancer was held on May 5, 2013, at San Diego, CA, to consider clinical trial design for this disease. The panel consisted of recognized experts from urology, medical oncology, radiation oncology, industry, and patient representatives, along with FDA officials. The discussion was facilitated by Jonathan P. Jarow, M.D., Medical Officer from the Office of Oncology Drug Products at FDA’s Center for Drug Evaluation and Research. The workshop focused on identifying pathways for the development of new products for the treatment of localized prostate cancer with a special focus on trial designs for each risk strata and potential surrogate endpoints that would be clinically meaningful. In addition, panelists identified key areas in which knowledge is limited and proposed areas that would benefit from further study. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.087
975
1. Trials that evaluate treatments for localized prostate cancer that utilize active surveillance as a comparator arm must balance the potential risk of disease progression if the risk strata are too high vs the potential overtreatment of clinically insignificant disease. Keeping this in mind, please describe the entry criteria that you would recommend for trials for this indication listing the specific risk factors (i.e., PSA, Gleason score, etc.) that you would employ and both the upper and lower limits for each risk factor. 2. The regulatory basis for full approval is demonstration of a clinical benefit, such as increased survival or an improvement in diseaserelated dysfunction or symptoms. Overall survival is not a practical endpoint for this patient population. What endpoint do you believe measures a clinically meaningful benefit? Please include in your discussion the duration of follow up necessary and magnitude of benefit that would be clinically meaningful for your proposed endpoint. 3. What should be the eligibility criteria for entry in a focal therapy study? Please include in your discussion your assessment of the scientific basis of focal therapy for either minimal disease or intermediate risk patients. 4. What should be the eligibility criteria for study entry for patients who have received definitive radiation therapy? Please discuss how you would identify a patient as having failed definitive radiation therapy and the procedure(s) that should be used to rule out metastatic disease. In your discussion of eligibility criteria, also address whether there is a need for intervention for all patients with failure of definitive radiation or would you restrict treatment to a subpopulation based on findings at the time of original diagnosis. For instance, would you exclude patients at either end of the risk strata based on findings at original diagnosis due to either minimal risk of cancer-related morbidity/mortality or a high likelihood of occult metastatic disease? 5. What should be the comparator arm for radiation therapy failure trials? 6. What endpoint should be employed for radiation failure trials? Discuss the minimum duration of follow up and magnitude of benefit that may be clinically meaningful? 7. What are the optimal patient population and endpoint that should be used for radiation therapy failure trials? Include in your discussion the effect of the primary treatment (surgery vs radiation) and mechanism of action of the adjuvant therapy (hormonal vs nonhormonal) on the choice of endpoint. 8. What endpoint should be employed to determine the efficacy of treatments that do not remove the prostate? Include in your discussion the effect of the comparator arm (surgery vs radiation therapy) on the choice of endpoint, minimum duration of follow up, and magnitude of benefit that would be clinically meaningful. Figure 1. Food and Drug Administration questions for panel members.
MATERIALS AND METHODS The workshop consisted of 3 formal presentations by panel members covering the following topics; regulatory basis of drug and biologics approval, regulatory basis of device approvals, and review of the development of patient-reported outcome (PRO) measures to assess clinical benefit. These presentations were followed by discussion of 8 specific questions posed by the FDA (Fig. 1). The FDA questions also served as a starting point for a wide-ranging discussion. FDA’s questions addressed clinical trial design elements with special focus on eligibility criteria, comparator(s) used, and endpoint(s) for development of products. The specific conditions discussed included the treatment of low-, intermediate-, and high-risk populations, focal therapies that do not remove the entire prostate gland (nonextirpative therapies), definitive 976
radiation therapy failure population, and adjuvant therapy for high-risk patients undergoing treatment with curative intent. The panel’s discussion and responses to the FDA questions are summarized in the following section.
RESULTS Treatment of Patients With Low-risk Localized Prostate Cancer Who Undergo Nonextirpative Therapies With Active Surveillance as the Comparator There was broad consensus that patients with very lowrisk prostate cancer, as defined by the National Comprehensive Cancer Network criteria, may not UROLOGY 83 (5), 2014
benefit from immediate treatment and, therefore, should not be included in trials.1 There was broad consensus that current commonly used categorical methods of classifying the disease risk levels are imperfect and that trials may use additional risk assessment tools (eg, Kattan’s nomogram, Cancer of the Prostate Risk Assessment score, or others).2,3 The discussion indicated that there has been a significant shift in the patients considered eligible for active surveillance. Most of the panel believed that at least some patients with intermediate-risk prostate cancer may be eligible for surveillance. Patient eligibility should include men with at least a 15- to 20-year life expectancy. There was discussion as to whether trials should also be restricted to men younger than 65 years. Discussion of using overall survival as an endpoint concluded that it was not feasible and that the vast majority of deaths would likely be because of comorbidities. There was discussion by the panel regarding the development of a PRO to assess clinical benefit.4 It was concluded that it would be extremely difficult to measure improvement in disease-related symptoms in an asymptomatic population. Moreover, the time and cost involved with development of a new PRO fit for purpose in this clinical setting was thought be discouraging. There was also discussion of using a PRO to measure the side effects of therapy that would be used to document superiority of a new therapy to current standard of care (eg, radiation therapy or surgery). The panel, however, could not agree on an oncological endpoint that would be used to assure that the new therapy maintains efficacy. The panel had difficulty identifying a practical measure of clinical benefit that would be a surrogate for overall survival or that would be meaningful, in itself, for patients with low-risk prostate cancer. Various discussed endpoints included measures of disease progression such as progression to T3, 33% of biopsy cores positive with disease, or presence of Gleason pattern 4-5, especially primary pattern 4 or 5. Other endpoints discussed included absence of cancer on prostate biopsy of sufficient duration and reduction of surgical intervention. Time to clinical intervention was felt by most panel members to be clinically meaningful but extremely difficult to assess in an unblinded trial. There was no consensus around any one endpoint that would be earlier in the disease process than time to metastasis, and there was concern that use of this endpoint may not be practical because of time constraints. The limitations of prostate-specific antigen (PSA) as a marker of progression or recurrence were discussed.
Focal Therapy The panel agreed that very low risk and most low risk patients should not be included in trials of these therapies.5 UROLOGY 83 (5), 2014
There was discussion about the utility of focal therapy in patients with well-defined unifocal disease; however, the panel could not agree on what constitutes unifocal disease. Moreover, there was no consensus on how to manage patients with focal disease of higher grade with a microfocus of low-risk disease on the contralateral side. There was general consensus that magnetic resonance imaging, as used at the time of the workshop, and circulating tumor cells are not yet sufficiently accurate in early stage prostate cancer to be used for patient selection or to monitor the course of the disease. The majority of the panel thought that patients with intermediate- to high-risk cancers were potential candidates for focal therapy and could be used to enrich for endpoint events. A noninferiority trial design comparing focal therapy with surgery or radiation therapy was discussed. There was general agreement, however, that this approach is hampered by the lack of data on the true effect size of these treatments, as measured against no therapy, which is required to establish a noninferiority margin.6,7 Local Therapy for Patients With Recurrence After Definitive Radiation Therapy There was broad consensus by the panel that, to be eligible, patients should have both a positive biopsy and biochemical progression >2 years after therapy. There was consensus that metastatic disease should be excluded by appropriate radiologic imaging (eg, computed tomography and/or magnetic resonance imaging, bone scan, or newer imaging techniques). There was little or no consensus on how to define biochemical progression. Most panelists preferred the use of Phoenix criteria, whereas others thought ASTRO criteria should be used in this setting. Although these criteria are acceptable for endpoints of studies to evaluate the efficacy of radiation therapy, some panelists thought that a positive prostate biopsy >2 years after radiation in the context of a rising PSA (whether the PSA meets the Phoenix or ASTRO criteria) is sufficient. All panelists thought that patients who experienced severe radiation toxicity should be excluded for subsequent ablative therapies. Some believed that patients who received high dose brachytherapy should also be excluded. There was discussion regarding the use of PSA doubling times to determine risk of subsequent clinical events.8 Important caveats discussed regarding PSA doubling time included that (1) it is unreliable in patients with low absolute PSA values, (2) it may not be interpretable if patients received previous hormone therapy (especially during a time of androgen recovery), and (3) there was discussion regarding the lack of standardization for the calculation of PSA doubling time in most trials. 977
There was discussion of whether risk factors at original diagnosis should be used to either include or exclude patients in trials without developing a consensus. There was discussion regarding the comparator arm for these trials. Most panel members thought it should be standard of care, which is some form of hormone therapy, continuous or intermittent. However, it was pointed out by several panel members that the evidence for the current hormonal standard of care is not strong. The panel discussed endpoints, and there was consensus that metastasis-free survival may be the most clinically meaningful surrogate for overall survival but may only be practical in populations enriched for high-risk disease. Adjuvant Therapy There was discussion about whether this is a worthwhile approach for patients undergoing surgery because standard use of PSA detects failures very early, and therapy could be administered at that time to only those patients who needed it. The panel agreed that only higher risk patients were candidates for further studies. The panel discussed potential endpoints to be used. The majority felt that metastasis-free survival was a clinically meaningful and practical endpoint.9,10 Symptomatic metastasis-free survival was also discussed as a clinically meaningful endpoint; however, this endpoint may not be feasible because of the difficulties in PRO development and administration. In addition, there is a significant chance of confounding by subsequent therapies before patients develop symptomatic metastases. Intermediate- and High-risk Patient Population Undergoing Nonextirpative Therapy There was a great deal of discussion on this topic with little consensus achieved. Many panel members favored the use of surgery as a comparator, but others suggested either cryotherapy or radiation therapy as comparators. Most panel members favored using time to metastasis as the primary endpoint; however, even this intermediate endpoint would likely require a lengthy and costly trial that might inhibit development of novel therapeutics by commercial sponsors. Some panel members favored disease-free survival but could not provide specific criteria to define this. It was noted that PSA recurrence is not appropriate as an endpoint, given that some PSA recurrences are associated with slow doubling times and have little or no clinical relevance.
CONCLUSION Summaries and presentations from this workshop are posted on the FDA Web site (http://www.fda.gov/Drugs/ NewsEvents/ucm348372.htm). The panel members’ conclusions will be discussed at subsequent ODAC 978
meetings and will inform any future FDA’s guidance on prostate cancer product development. Ultimately, FDA intends to work toward establishing a set of principles that can be used to facilitate the development of drugs and devices used in the management of patients with localized prostate cancer. References 1. National Comprehensive Cancer Network Prostate Cancer Treatment Guidelines http://www.nccn.org/professionals/physician_gls/f_ guidelines_nojava.asp#site. 2. Eggener SE, Scardino PT, Walsh PC, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol. 2011;185:869-875. 3. Cooperberg MR, Freedland SJ, Pasta DJ, et al. Multi-institutional validation of the UCSF Cancer of the Prostate Risk Assessment for prediction of recurrence after radical prostatectomy. Cancer. 2006; 107:2384-2391. 4. Calvert M, Blazeby J, Altman DG, et al; CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309:814-822. 5. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term followup of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28:126-131. 6. Piaggio G, Elbourne DR, Pocock SJ, et al; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308: 2594-2604. 7. FDA Guidance for Industry: Non-Inferiority Clinical Trials www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM202140.pdf. 8. Klayton TL, Ruth K, Buyyounouski MK, et al. PSA doubling time predicts for the development of distant metastases for patients who fail 3DCRT or IMRT using the phoenix definition. Pract Radiat Oncol. 2011;1:235-242. 9. Antonarakis ES, Chen Y, Elsamanoudi SI, et al. Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database. BJU Int. 2011;108:378. 10. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. 2013.
EDITORIAL COMMENT This article highlights the U.S. Food and Drug Administration (FDA) and American Urological Association workshop on drug and device development for localized prostate cancer, which was held at the American Urological Association Annual Meeting in San Diego in May 2013. This forum represented a landmark public event to discuss key issues and engage in important dialogue surrounding the treatment of localized prostate cancer, in particular focused on trial design and other issues that surround future therapeutics in early prostate cancer. In localized prostate cancer, we should consider ourselves fortunate for the prolonged natural history of early prostate cancer, a natural history that is the driving force for the extended life expectancy of our patients, even in those with recurrent disease after primary curative therapy. However, this natural history is our Achilles’ heel in the design and implementation of clinical trials with meaningful endpoints. Specifically, this creeping natural history hampers our efforts in trial design. This was most clearly revealed in the forum discussions regarding UROLOGY 83 (5), 2014
low-risk prostate cancer and active surveillance. Although it is no longer the question of “if” one should recommend active surveillance, the focal point of our interests in this disease state has shifted to “how” and “how to improve” active surveillance. Level I, randomized controlled evidence has provided evidence of equipoise between surveillance vs treatments with curative intent1; important messages of the forum were that active surveillance is the appropriate comparator arm for all trials of lowrisk prostate cancer and that we must not engage in head-to-head trials of active treatments without first embarking on trials of these treatments compared with nontreatment. Nevertheless, we are still left with the conundrum of the prolonged natural history of low-risk disease, the vagaries surrounding what constitutes “progression” on active surveillance, and perhaps the most troublesome question of what is the appropriate, clinically meaningful endpoint for active surveillance trials. Although the FDA gold standard trial endpoint has primarily been overall survival, the key question is whether modalities or interventions that affect more proximal endpoints, for example, metastasis-free survival, would ever be deemed meritorious in the eyes of the regulatory bodies that approve new therapeutics for clinical use and reimbursement. There is no doubt that the forum served to augment our field’s interface with the FDA and also provided a timely interchange in this era of comparative
UROLOGY 83 (5), 2014
effectiveness research imperatives. In closing, this important forum provided the necessary introduction for future forums which have already been planned to focus on the devices and biomarkers that are being intensively studied and developed in the academic and commercial space and those that will be discussed in a imminent public forum, jointly sponsored by the Society of Urologic Oncology and the National Institutes of Health Prostate Cancer Specialized Programs of Research Excellence community. For now, we must embrace the willingness of the FDA to engage our specialty and must always remain cognizant of the importance of having a seat at the table with our federal colleagues. Daniel W. Lin, M.D., University of Washington, Seattle, WA
Reference 1. Wilt TJ, Brawer MK, Jones KM, et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203-213.
http://dx.doi.org/10.1016/j.urology.2013.10.088 UROLOGY 83: 978e979, 2014. Published by Elsevier Inc.
979
T
he U.S. Food and Drug Administration (FDA) has partnered with the American Urological Association to hold public workshops evaluating potential trial designs for product development (drugs, biologics, and devices) for the treatment of localized genitourinary cancers. These workshops are designed to engage key opinion leaders and stakeholders who understand the unique problems associated with trial
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, MD; the Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX; the Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD; the Division of Biometrics V, Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD; the Department of Surgery, David H. Koch Chair, Memorial Sloan-Kettering Cancer Center, New York, NY; the Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; the University of Connecticut Health Center, Farmington, CT; Johns Hopkins School of Medicine, Baltimore, MD; the American Cancer Society, Emory University, Atlanta, GA; Laborde Professor for Cancer Research, Departments of Medicine and Urology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA; Ronald H. Bloom Chair in Cancer Therapeutics, Department of Radiation Oncology, CedarsSinai Medical Center, Los Angeles, CA; Board Chairman Emeritus, Us TOO, International, Des Plaines, IL; and the American Medical Systems, Minnetonka, MN Reprint requests: Jonathan P. Jarow, M.D., Office of Hematology and Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993. E-mail: [email protected] Submitted: October 18, 2013, accepted (with revisions): October 20, 2013
Published by Elsevier Inc.
design and product development for these diseases. Issues highlighted at these workshops will be brought to the Oncologic Drugs Advisory Committee (ODAC), FDA’s statutory advisory body for review of oncology drugs. Discussions at both the workshops and ODAC will inform guidance that FDA is preparing on clinical trial design for localized prostate cancer product approvals. A workshop on localized prostate cancer was held on May 5, 2013, at San Diego, CA, to consider clinical trial design for this disease. The panel consisted of recognized experts from urology, medical oncology, radiation oncology, industry, and patient representatives, along with FDA officials. The discussion was facilitated by Jonathan P. Jarow, M.D., Medical Officer from the Office of Oncology Drug Products at FDA’s Center for Drug Evaluation and Research. The workshop focused on identifying pathways for the development of new products for the treatment of localized prostate cancer with a special focus on trial designs for each risk strata and potential surrogate endpoints that would be clinically meaningful. In addition, panelists identified key areas in which knowledge is limited and proposed areas that would benefit from further study. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.087
975
1. Trials that evaluate treatments for localized prostate cancer that utilize active surveillance as a comparator arm must balance the potential risk of disease progression if the risk strata are too high vs the potential overtreatment of clinically insignificant disease. Keeping this in mind, please describe the entry criteria that you would recommend for trials for this indication listing the specific risk factors (i.e., PSA, Gleason score, etc.) that you would employ and both the upper and lower limits for each risk factor. 2. The regulatory basis for full approval is demonstration of a clinical benefit, such as increased survival or an improvement in diseaserelated dysfunction or symptoms. Overall survival is not a practical endpoint for this patient population. What endpoint do you believe measures a clinically meaningful benefit? Please include in your discussion the duration of follow up necessary and magnitude of benefit that would be clinically meaningful for your proposed endpoint. 3. What should be the eligibility criteria for entry in a focal therapy study? Please include in your discussion your assessment of the scientific basis of focal therapy for either minimal disease or intermediate risk patients. 4. What should be the eligibility criteria for study entry for patients who have received definitive radiation therapy? Please discuss how you would identify a patient as having failed definitive radiation therapy and the procedure(s) that should be used to rule out metastatic disease. In your discussion of eligibility criteria, also address whether there is a need for intervention for all patients with failure of definitive radiation or would you restrict treatment to a subpopulation based on findings at the time of original diagnosis. For instance, would you exclude patients at either end of the risk strata based on findings at original diagnosis due to either minimal risk of cancer-related morbidity/mortality or a high likelihood of occult metastatic disease? 5. What should be the comparator arm for radiation therapy failure trials? 6. What endpoint should be employed for radiation failure trials? Discuss the minimum duration of follow up and magnitude of benefit that may be clinically meaningful? 7. What are the optimal patient population and endpoint that should be used for radiation therapy failure trials? Include in your discussion the effect of the primary treatment (surgery vs radiation) and mechanism of action of the adjuvant therapy (hormonal vs nonhormonal) on the choice of endpoint. 8. What endpoint should be employed to determine the efficacy of treatments that do not remove the prostate? Include in your discussion the effect of the comparator arm (surgery vs radiation therapy) on the choice of endpoint, minimum duration of follow up, and magnitude of benefit that would be clinically meaningful. Figure 1. Food and Drug Administration questions for panel members.
MATERIALS AND METHODS The workshop consisted of 3 formal presentations by panel members covering the following topics; regulatory basis of drug and biologics approval, regulatory basis of device approvals, and review of the development of patient-reported outcome (PRO) measures to assess clinical benefit. These presentations were followed by discussion of 8 specific questions posed by the FDA (Fig. 1). The FDA questions also served as a starting point for a wide-ranging discussion. FDA’s questions addressed clinical trial design elements with special focus on eligibility criteria, comparator(s) used, and endpoint(s) for development of products. The specific conditions discussed included the treatment of low-, intermediate-, and high-risk populations, focal therapies that do not remove the entire prostate gland (nonextirpative therapies), definitive 976
radiation therapy failure population, and adjuvant therapy for high-risk patients undergoing treatment with curative intent. The panel’s discussion and responses to the FDA questions are summarized in the following section.
RESULTS Treatment of Patients With Low-risk Localized Prostate Cancer Who Undergo Nonextirpative Therapies With Active Surveillance as the Comparator There was broad consensus that patients with very lowrisk prostate cancer, as defined by the National Comprehensive Cancer Network criteria, may not UROLOGY 83 (5), 2014
benefit from immediate treatment and, therefore, should not be included in trials.1 There was broad consensus that current commonly used categorical methods of classifying the disease risk levels are imperfect and that trials may use additional risk assessment tools (eg, Kattan’s nomogram, Cancer of the Prostate Risk Assessment score, or others).2,3 The discussion indicated that there has been a significant shift in the patients considered eligible for active surveillance. Most of the panel believed that at least some patients with intermediate-risk prostate cancer may be eligible for surveillance. Patient eligibility should include men with at least a 15- to 20-year life expectancy. There was discussion as to whether trials should also be restricted to men younger than 65 years. Discussion of using overall survival as an endpoint concluded that it was not feasible and that the vast majority of deaths would likely be because of comorbidities. There was discussion by the panel regarding the development of a PRO to assess clinical benefit.4 It was concluded that it would be extremely difficult to measure improvement in disease-related symptoms in an asymptomatic population. Moreover, the time and cost involved with development of a new PRO fit for purpose in this clinical setting was thought be discouraging. There was also discussion of using a PRO to measure the side effects of therapy that would be used to document superiority of a new therapy to current standard of care (eg, radiation therapy or surgery). The panel, however, could not agree on an oncological endpoint that would be used to assure that the new therapy maintains efficacy. The panel had difficulty identifying a practical measure of clinical benefit that would be a surrogate for overall survival or that would be meaningful, in itself, for patients with low-risk prostate cancer. Various discussed endpoints included measures of disease progression such as progression to T3, 33% of biopsy cores positive with disease, or presence of Gleason pattern 4-5, especially primary pattern 4 or 5. Other endpoints discussed included absence of cancer on prostate biopsy of sufficient duration and reduction of surgical intervention. Time to clinical intervention was felt by most panel members to be clinically meaningful but extremely difficult to assess in an unblinded trial. There was no consensus around any one endpoint that would be earlier in the disease process than time to metastasis, and there was concern that use of this endpoint may not be practical because of time constraints. The limitations of prostate-specific antigen (PSA) as a marker of progression or recurrence were discussed.
Focal Therapy The panel agreed that very low risk and most low risk patients should not be included in trials of these therapies.5 UROLOGY 83 (5), 2014
There was discussion about the utility of focal therapy in patients with well-defined unifocal disease; however, the panel could not agree on what constitutes unifocal disease. Moreover, there was no consensus on how to manage patients with focal disease of higher grade with a microfocus of low-risk disease on the contralateral side. There was general consensus that magnetic resonance imaging, as used at the time of the workshop, and circulating tumor cells are not yet sufficiently accurate in early stage prostate cancer to be used for patient selection or to monitor the course of the disease. The majority of the panel thought that patients with intermediate- to high-risk cancers were potential candidates for focal therapy and could be used to enrich for endpoint events. A noninferiority trial design comparing focal therapy with surgery or radiation therapy was discussed. There was general agreement, however, that this approach is hampered by the lack of data on the true effect size of these treatments, as measured against no therapy, which is required to establish a noninferiority margin.6,7 Local Therapy for Patients With Recurrence After Definitive Radiation Therapy There was broad consensus by the panel that, to be eligible, patients should have both a positive biopsy and biochemical progression >2 years after therapy. There was consensus that metastatic disease should be excluded by appropriate radiologic imaging (eg, computed tomography and/or magnetic resonance imaging, bone scan, or newer imaging techniques). There was little or no consensus on how to define biochemical progression. Most panelists preferred the use of Phoenix criteria, whereas others thought ASTRO criteria should be used in this setting. Although these criteria are acceptable for endpoints of studies to evaluate the efficacy of radiation therapy, some panelists thought that a positive prostate biopsy >2 years after radiation in the context of a rising PSA (whether the PSA meets the Phoenix or ASTRO criteria) is sufficient. All panelists thought that patients who experienced severe radiation toxicity should be excluded for subsequent ablative therapies. Some believed that patients who received high dose brachytherapy should also be excluded. There was discussion regarding the use of PSA doubling times to determine risk of subsequent clinical events.8 Important caveats discussed regarding PSA doubling time included that (1) it is unreliable in patients with low absolute PSA values, (2) it may not be interpretable if patients received previous hormone therapy (especially during a time of androgen recovery), and (3) there was discussion regarding the lack of standardization for the calculation of PSA doubling time in most trials. 977
There was discussion of whether risk factors at original diagnosis should be used to either include or exclude patients in trials without developing a consensus. There was discussion regarding the comparator arm for these trials. Most panel members thought it should be standard of care, which is some form of hormone therapy, continuous or intermittent. However, it was pointed out by several panel members that the evidence for the current hormonal standard of care is not strong. The panel discussed endpoints, and there was consensus that metastasis-free survival may be the most clinically meaningful surrogate for overall survival but may only be practical in populations enriched for high-risk disease. Adjuvant Therapy There was discussion about whether this is a worthwhile approach for patients undergoing surgery because standard use of PSA detects failures very early, and therapy could be administered at that time to only those patients who needed it. The panel agreed that only higher risk patients were candidates for further studies. The panel discussed potential endpoints to be used. The majority felt that metastasis-free survival was a clinically meaningful and practical endpoint.9,10 Symptomatic metastasis-free survival was also discussed as a clinically meaningful endpoint; however, this endpoint may not be feasible because of the difficulties in PRO development and administration. In addition, there is a significant chance of confounding by subsequent therapies before patients develop symptomatic metastases. Intermediate- and High-risk Patient Population Undergoing Nonextirpative Therapy There was a great deal of discussion on this topic with little consensus achieved. Many panel members favored the use of surgery as a comparator, but others suggested either cryotherapy or radiation therapy as comparators. Most panel members favored using time to metastasis as the primary endpoint; however, even this intermediate endpoint would likely require a lengthy and costly trial that might inhibit development of novel therapeutics by commercial sponsors. Some panel members favored disease-free survival but could not provide specific criteria to define this. It was noted that PSA recurrence is not appropriate as an endpoint, given that some PSA recurrences are associated with slow doubling times and have little or no clinical relevance.
CONCLUSION Summaries and presentations from this workshop are posted on the FDA Web site (http://www.fda.gov/Drugs/ NewsEvents/ucm348372.htm). The panel members’ conclusions will be discussed at subsequent ODAC 978
meetings and will inform any future FDA’s guidance on prostate cancer product development. Ultimately, FDA intends to work toward establishing a set of principles that can be used to facilitate the development of drugs and devices used in the management of patients with localized prostate cancer. References 1. National Comprehensive Cancer Network Prostate Cancer Treatment Guidelines http://www.nccn.org/professionals/physician_gls/f_ guidelines_nojava.asp#site. 2. Eggener SE, Scardino PT, Walsh PC, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol. 2011;185:869-875. 3. Cooperberg MR, Freedland SJ, Pasta DJ, et al. Multi-institutional validation of the UCSF Cancer of the Prostate Risk Assessment for prediction of recurrence after radical prostatectomy. Cancer. 2006; 107:2384-2391. 4. Calvert M, Blazeby J, Altman DG, et al; CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309:814-822. 5. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term followup of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28:126-131. 6. Piaggio G, Elbourne DR, Pocock SJ, et al; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308: 2594-2604. 7. FDA Guidance for Industry: Non-Inferiority Clinical Trials www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM202140.pdf. 8. Klayton TL, Ruth K, Buyyounouski MK, et al. PSA doubling time predicts for the development of distant metastases for patients who fail 3DCRT or IMRT using the phoenix definition. Pract Radiat Oncol. 2011;1:235-242. 9. Antonarakis ES, Chen Y, Elsamanoudi SI, et al. Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database. BJU Int. 2011;108:378. 10. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. 2013.
EDITORIAL COMMENT This article highlights the U.S. Food and Drug Administration (FDA) and American Urological Association workshop on drug and device development for localized prostate cancer, which was held at the American Urological Association Annual Meeting in San Diego in May 2013. This forum represented a landmark public event to discuss key issues and engage in important dialogue surrounding the treatment of localized prostate cancer, in particular focused on trial design and other issues that surround future therapeutics in early prostate cancer. In localized prostate cancer, we should consider ourselves fortunate for the prolonged natural history of early prostate cancer, a natural history that is the driving force for the extended life expectancy of our patients, even in those with recurrent disease after primary curative therapy. However, this natural history is our Achilles’ heel in the design and implementation of clinical trials with meaningful endpoints. Specifically, this creeping natural history hampers our efforts in trial design. This was most clearly revealed in the forum discussions regarding UROLOGY 83 (5), 2014
low-risk prostate cancer and active surveillance. Although it is no longer the question of “if” one should recommend active surveillance, the focal point of our interests in this disease state has shifted to “how” and “how to improve” active surveillance. Level I, randomized controlled evidence has provided evidence of equipoise between surveillance vs treatments with curative intent1; important messages of the forum were that active surveillance is the appropriate comparator arm for all trials of lowrisk prostate cancer and that we must not engage in head-to-head trials of active treatments without first embarking on trials of these treatments compared with nontreatment. Nevertheless, we are still left with the conundrum of the prolonged natural history of low-risk disease, the vagaries surrounding what constitutes “progression” on active surveillance, and perhaps the most troublesome question of what is the appropriate, clinically meaningful endpoint for active surveillance trials. Although the FDA gold standard trial endpoint has primarily been overall survival, the key question is whether modalities or interventions that affect more proximal endpoints, for example, metastasis-free survival, would ever be deemed meritorious in the eyes of the regulatory bodies that approve new therapeutics for clinical use and reimbursement. There is no doubt that the forum served to augment our field’s interface with the FDA and also provided a timely interchange in this era of comparative
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effectiveness research imperatives. In closing, this important forum provided the necessary introduction for future forums which have already been planned to focus on the devices and biomarkers that are being intensively studied and developed in the academic and commercial space and those that will be discussed in a imminent public forum, jointly sponsored by the Society of Urologic Oncology and the National Institutes of Health Prostate Cancer Specialized Programs of Research Excellence community. For now, we must embrace the willingness of the FDA to engage our specialty and must always remain cognizant of the importance of having a seat at the table with our federal colleagues. Daniel W. Lin, M.D., University of Washington, Seattle, WA
Reference 1. Wilt TJ, Brawer MK, Jones KM, et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203-213.
http://dx.doi.org/10.1016/j.urology.2013.10.088 UROLOGY 83: 978e979, 2014. Published by Elsevier Inc.
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