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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Cancer. 2017 Dec 20;124(7):1383–1390. doi: 10.1002/cncr.31204

Low Testosterone at First PSA Failure and Assessment of the Risk of Death in Men with Unfavorable-Risk Prostate Cancer Treated on Prospective Clinical Trials

Katelyn M Atkins 1, Ming-Hui Chen 2, Jing Wu 3, Andrew A Renshaw 4, Marian Loffredo 5, Philip W Kantoff 6, Eric J Small 7, Anthony V D’Amico 5
PMCID: PMC6034656  NIHMSID: NIHMS968347  PMID: 29266181

Abstract

BACKGROUND

Low testosterone at prostate cancer (PC) diagnosis has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at first PSA failure has not been elucidated and was studied.

METHODS

Between 1995–2001, 58 men with unfavorable-risk PC treated on clinical trials with radiation and androgen deprivation therapy (ADT) had testosterone levels at PSA failure available. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific, other-cause and all-cause mortality (PCSM, OCM, ACM) adjusting for age, salvage ADT and known PC prognostic factors.

RESULTS

After a median follow-up of 6.68 years following PSA failure, 31 men (53.4%) died; 10 from PC (32.3%), of which 8/11 (72.7%) versus 2/47 (4.3%) occurred in men with low versus normal testosterone at PSA failure, respectively. A significant increase in the risk of ACM (adjusted hazard ratio, AHR[2.54, 95%CI 1.04–6.21]; P=0.04) and PCSM (AHR[13.71, 95%CI 2.4–78.16]; P=0.003), with a reciprocal trend toward decreased risk of OCM (AHR[0.18, 95%CI 0.02–1.55]; P=0.12) was observed in men with low versus normal testosterone.

CONCLUSION

Low, but not necessarily castrate, testosterone levels at PSA failure confers a very poor prognosis. These observations provide evidence to support testosterone testing at PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides rationale supporting their use with ADT in men with low testosterone in the setting of a phase II trial.

Keywords: prostate cancer, testosterone, biochemical failure, PSA failure, death

INTRODUCTION

Several prospective randomized clinical trials have demonstrated that the addition of androgen deprivation therapy (ADT) to external beam radiation therapy (RT) prolongs prostate cancer (PC)-specific and overall survival in men treated for intermediate- or high-risk PC1–3. However, despite definitive management, up to one third of these men will experience biochemical failure4. The standard of care for prostate-specific antigen (PSA) failure following definitive RT is salvage ADT, most commonly using a luteinizing hormone-releasing hormone (LHRH) agonist5; although no prospective, randomized trials have been conducted to determine a survival benefit with salvage ADT compared to observation in men with PSA-only recurrence. Moreover, the clinical course to metastasis and death from PC following PSA failure is quite variable. While associated prognostic factors such as PSA doubling time (PSA DT), interval to PSA failure, and biopsy Gleason score4,6 have been identified, there remains a need for determination of additional prognostic and predictive factors to further personalize optimal salvage therapy.

Therapeutic targeting of the androgen receptor signaling axis remains a mainstay of current treatment strategies. Indeed, the use of the novel anti-androgens enzalutamide and abiraterone and the chemotherapeutic agent docetaxel have been shown to prolong survival in men with metastatic castrate-resistant PC7–9, while abiraterone10,11 and docetaxel12,13 added to standard ADT have been shown to prolong survival in men with newly diagnosed metastatic castrate-sensitive PC and possibly high-risk localized PC11,13,14 compared to conventional ADT alone. Moreover, while it has been demonstrated that low testosterone at presentation is associated with more aggressive tumors, poorer prognosis after radical prostatectomy (RP), and shorter responses to ADT15–18, the impact on survival of low testosterone and how to define the best treatment approach at first PSA failure has not been elucidated.

This study aimed to evaluate men enrolled on a prospective trial with unfavorable-risk PC treated with definitive RT and ADT, to determine whether low testosterone at first PSA failure and prior to the documentation of metastatic disease was associated with an increased risk of PC-specific and all-cause mortality (PCSM, ACM), adjusting for age, salvage ADT use and known PC prognostic factors. If such an association existed, then low testosterone levels at first PSA failure could be used to identify men who are optimal candidates for enrollment onto prospective trials testing the addition of novel therapeutic agents to ADT, including agents shown to prolong survival in patients with metastatic castrate-sensitive, castrate-resistant, or high-risk localized PC7–14.

MATERIAL AND METHODS

Patient Population and Treatment

The 58 patients in this study were enrolled on one of two prospective clinical trials, for which a complete description of eligibility criteria, treatment specifications, and patient characteristics have been reported previously1,19. In the first (NCT00002889), 180 men with 1992 American Joint Commission on Cancer (AJCC) clinical stage T1c-T3cN0M0 PC were enrolled onto a phase II Cancer and Leukemia Group B Study (CALGB 9682) evaluating the prognostic significance of endorectal magnetic resonance imaging (eMRI)-defined tumor volume changes in men treated with definitive RT and ADT between May 31, 1997, and April 30, 2001. In the second study (NCT00116220), 206 men with 1992 AJCC clinical stage T1b-T2bNXM0 PC were randomized to receive RT with or without 6 months of ADT between December 7, 1995, and December 27, 2001. Only the men on the ADT arm were eligible for inclusion in the current study. For both studies, centralized pathology review was performed by a dedicated genitourinary pathologist. All 58 men in this study were treated with RT and ADT, consisting of 6 months of an LHRH agonist (leuprolide acetate, 7.5 mg monthly or 22.5 mg every 3 months; or goserelin, 3.6 mg monthly or 10.8 mg every 3 months) and a non-steroidal anti-androgen (flutamide, 250 mg every 8 hours). External beam RT was delivered to the prostate and seminal vesicles using a three-dimensional conformal technique, prescribed to an isocenter that received 45 Gy in 25 1.8-Gy fractions followed by a boost volume that received 21.6–22 Gy delivered in 11–12 1.8–2.0-Gy fractions, normalized to 95%.

A PSA rise of at least 2 ng/mL above nadir was achieved prior to initiation of salvage therapy in all patients, meeting the 2006 Phoenix definition of PSA failure following radiation therapy20. Salvage therapy generally consisted of an LHRH agonist. Of the subset of 180 and 206 men from CALGB 9682 and the RCT, respectively, who experienced PSA failure and received salvage ADT, 58 men (n=4 from CALGB 9682 alone; n=54 from the RCT, who were also eligible for co-enrollment onto CALGB 9682) had total serum testosterone levels at first PSA failure available and thereby defined our study cohort (Figure 1). Serum testosterone was measured centrally using the Bayer Assay (Tarrytown, NY), with low testosterone defined as <280 ng/dL (lower limit of normal for this assay). This retrospective review was approved by the Dana-Farber Cancer Institute institutional review board.

Figure 1.

Figure 1

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CONSORT diagram of patient eligibility and selection. CALGB, Cancer and Leukemia Group B; RCT, randomized controlled trial; ADT, androgen deprivation therapy; PSA, prostate-specific antigen.

Follow-up and Determination of the Cause of Death

In CALGB 9682, men were seen in follow-up every six months for three years and annually thereafter, while in the RCT, men were seen every three months for the first two years, every six months for the subsequent three years, and yearly thereafter. Each follow-up visit included a history and physical exam, with serum PSA levels obtained prior to digital rectal examination. At first PSA failure, a restaging bone scan and pelvic computed tomography (CT) or MRI were obtained. No men were lost to follow-up. The cause of death was determined by the patient’s primary oncologist. Death from PC was defined as those men who had castrate-resistant metastatic disease and a rising PSA despite salvage ADT regimens and/or chemotherapy at the time of death.

Statistical Methods

Distribution and Comparison of Clinical Characteristics

Descriptive statistics were used to report the distribution of clinical characteristics amongst men with low versus normal testosterone at first PSA failure and are displayed in Table 1. The clinical factors including PSA DT, interval to PSA failure, age at PSA failure, and interval to salvage ADT following PSA failure had median and interquartile ranges calculated and compared across the two testosterone subgroups. For the continuous covariates (PSA DT, interval to PSA failure, and age at PSA failure), comparisons were evaluated using a Wilcoxon rank sum test21, whereas interval to salvage ADT following PSA failure and the median survival were calculated using the Kaplan–Meier method and comparisons were made using the log-rank test22. The categorical covariate of Gleason score (≤6, 7, 8–10) was compared using a Fisher’s exact test23.

Table 1.

Distribution and comparison of clinical characteristics stratified by low or normal testosterone at PSA failure

Clinical characteristic Testosterone
Low (n=11) Normal (n=47) P-value
PSA DT, median (IQR, months) 2.79 (2.11, 4.42) 10.59 (6.84, 22.0) 0.001
Int to PSA failure, median (IQR, months) 24.35 (14.49, 52.67) 41.20 (25.53, 55.03) 0.08
Age at PSA failure, median (IQR, years) 76.33 (73.09, 79.53) 73.63 (69.34, 79.07) 0.25
Int to salvage ADT following PSA failure, median (IQR, months) 10.87 (5.29, 12.98) 15.63 (6.7, 21.82) 0.11
Highest Gleason score
 8–10 (n, %) 6 (54.5%) 12 (25.5%) 0.04
 7 (n, %) 5 (45.5%) 20 (42.6%)
 ≤6 (n, %) 0 (0%) 15 (31.9%)
Median survival time (IQR, years) 4.06 (3.28, 8.45) 7.55 (3.96, 15.05) 0.046
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Abbreviations: DT, doubling time; IQR, interquartile range; Int, interval; ADT, androgen deprivation therapy; PSA, prostate-specific antigen. The distributions of continuous variables were compared using Wilcoxon rank sum test (PSA DT, interval to PSA failure, age at PSA failure) and log-rank test (interval to salvage ADT following PSA failure and median survival time). The categorical covariate of Gleason score (≤6, 7, 8–10) was compared using a Fisher’s exact test.

Cox and Competing Risks Regression

Univariate and multivariate Cox24 and Fine and Gray25 regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific, other-cause and all-cause mortality (PCSM, OCM, ACM) adjusting for age, salvage ADT use, and known PC prognostic factors. For the Fine and Gray competing-risks regressions, deaths due to causes other than the indicated endpoint were censored at the time of death and considered “competing risks”. For the model, time zero was the date of PSA failure and concluded by the date of death or last observation through January 22, 2015, whichever came first. Low versus normal testosterone level at first PSA failure and biopsy Gleason score (≤6, 7, 8–10) variables were treated as categorical covariates with baseline groups defined as low testosterone and Gleason score ≤6, respectively, whereas PSA DT, age at PSA failure, and interval to PSA failure variables were treated as continuous covariates. The use of salvage ADT was modeled as a time-dependent covariate, given that the interval from PSA failure to initiation of salvage ADT varied depending upon when the PSA level approached 10 ng/ml as per protocol specification. Unadjusted and adjusted hazard ratios were calculated for each covariate with associated 95% CI and P values (a 2-sided P value <.05 was considered statistically significant).

Estimates of ACM, PCSM, and OCM

One minus Kaplan–Meier (KM) estimates22 of ACM and cumulative incidence estimates26 of PCSM and OCM were calculated and graphically displayed, stratified by low or normal testosterone at first PSA failure. These estimates were compared using a 2-sided Gray’s P-value27 for PCSM and OCM and a log-rank 2-sided P-value for ACM. A 2-sided P value <.05 was considered statistically significant. SAS version 9.4 (SAS Institute; Cary, NC, USA) was used for all calculations except for those involving 2-sided Gray’s P-values, for which R version 3.2.3 (R Foundation; Auckland, New Zealand) was used.

RESULTS

Distribution and Comparison of Clinical Characteristics

As shown in Table 1, men with low testosterone at first PSA failure (median serum testosterone 162 ng/dL; range, 120 to 236 ng/dL) had less favorable clinical characteristics and median survival when compared to men with normal testosterone. Specifically, these men had a shorter median PSA DT (2.79 vs 10.59 months; P=0.001) and a greater proportion of highest Gleason score 8–10 (54.5% vs 25.5%, P=0.04). Men with low testosterone had a shorter median survival following PSA failure (4.06 vs 7.55 years; P=0.046). Among the 11 men with low testosterone at PSA failure, 4 (36.4%) also had low testosterone at PC diagnosis (Figure 1) with testosterone levels of 205, 198, 199 and 211 ng/dL and corresponding values of 127, 147, 157 and 201 ng/dL at PSA failure, respectively. When compared to the remaining subset of 11 men with low testosterone at PSA failure (n=7, 63.6%), these men had an increased risk of PCSM on univariate analysis (HR 1.41, 95% CI 0.38–5.25; P=0.61), although not significant likely due to limited power based on the small sample size.

Analysis of PCSM, ACM, and OCM

After a median follow-up of 6.68 (interquartile range, IQR, 3.87–13.71) years following PSA failure, 31 of 58 men (53.4%) died; 10 from PC (32.3%). Among the 10 PC deaths, 8/11 (72.7%) versus 2/47 (4.3%) occurred in men with low versus normal testosterone at first PSA failure, respectively (Table 2). After adjustment for age, salvage ADT use and known PC prognostic factors, a significant increase in both the risk of ACM (adjusted hazard ratio, AHR, 2.54, 95% CI 1.04–6.21; P=0.04) and PCSM (AHR 13.71, 95% CI 2.4–78.16; P=0.003), with a reciprocal trend toward decreased risk of OCM (AHR 0.18, 95% CI 0.02–1.55; P=0.12) was observed in men with low versus normal testosterone at first PSA failure.

Table 2.

Unadjusted and adjusted HRs for each clinical characteristic from the Cox-regression and competing risks analyses

Covariate No.
of
men		 All-cause mortality Prostate cancer-specific mortality Other-cause mortality
No.
of
ACD		 Univariate Multivariate No.
of
PCD		 Univariate Multivariate No.
of
OCD		 Univariate Multivariate
HR
(95%
CI)		 P-
value		 AHR (95%
CI)		 P-
value		 HR
(95%
CI)		 P-
value		 AHR
(95%
CI)		 P-
value		 HR
(95%
CI)		 P-
value		 AHR
(95%
CI)		 P-
value
Testosterone
Low 11 9 2.21 (0.99, 4.94) 0.05 2.54 (1.04,6.21) 0.04 8 21.69 (4.77, 98.56) <.0001 13.71 (2.4, 78.16) 0.003 1 0.13 (0.02, 0.97) 0.047 0.18 (0.02, 1.55) 0.12
Normal 47 22 1.0 (Ref) 1.0 (Ref) 2 20
PSA DT 58 31 1.01 (0.99, 1.03) 0.42 1.01 (0.99, 1.03) 0.43 10 0.88 (0.77, 1.0) 0.05 0.90 (0.78, 1.03) 0.12 21 1.03 (1.01, 1.05) 0.002 1.02 (0.99, 1.04) 0.18
Gleason
8–10 18 8 1.07 (0.47, 2.41) 0.88 1.42 (0.55, 3.69) 0.47 4 1.92 (0.56, 6.57) 0.30 0.32 (0.08, 1.23) 0.10 4 0.59 (0.20, 1.71) 0.33 1.24 (0.39, 3.94) 0.71
≤7 40 23 1.0 (Ref) 1.0 (Ref) 6 1.0 (Ref) 1.0 (Ref) 17 1.0 (Ref) 1.0 (Ref)
Age at PSA failure 58 31 1.07 (1.01, 1.13) 0.03 1.05 (0.98, 1.12) 0.17 10 1.06 (0.99, 1.13) 0.08 1.12 (0.97, 1.29) 0.12 21 1.04 (0.98, 1.10) 0.21 1.03 (0.97, 1.10) 0.33
Int to PSA failure 58 31 1.01 (1.0, 1.02) 0.09 1.01 (1.0, 1.02) 0.19 10 0.98 (0.95, 1.01) 0.22 0.97 (0.93, 1.01) 0.09 21 1.02 (1.01, 1.03) 0.001 1.01 (1.0, 1.02) 0.07
Int to salvage ADT (t) 58 31 1.11 (0.51, 2.40) 0.80 0.93 (0.37, 2.36) 0.89 10 3.57 (0.82, 15.52) 0.09 0.39 (0.03, 5.54) 0.49 21 0.50 (0.21, 1.16) 0.11 0.73 (0.31, 1.71) 0.47
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Abbreviations: PSA, prostate-specific antigen; DT, doubling time; Int, interval; ADT, androgen deprivation therapy; HR, hazard ratio; AHR, adjusted hazard ratio; No, number; ACD, all-cause deaths; PCD, prostate cancer deaths; OCD, other-cause deaths. Univariate and multivariate Cox (ACM) and Fine and Gray (PCSM and OCM) regressions were adjusted for known prostate cancer prognostic factors and the use of salvage ADT. Salvage ADT was modeled as a time-dependent covariate.

Estimates of PCSM, ACM, and OCM

Estimates of ACM, PCSM, and OCM stratified by low versus normal testosterone at first PSA failure are depicted in Figure 2, respectively. In men with low testosterone, there was a statistically significant increase in the estimates of ACM (P=0.046, Figure 2A) and PCSM (P<0.0001, Figure 2B), whereas there was a reciprocal decrease in OCM that approached statistical significance (P=0.0504, Figure 2C). Specifically, the 5-year point estimates of ACM, PCSM, and OCM, stratified by low versus normal testosterone at first PSA failure were 67.27% (95% CI 25.91–89.02%) vs 30.84% (95% CI 16.78–46.05%), 56.36% (95% CI 20.38–81.33%) vs 5.76% (95% CI 0.98–17.19%), and 10.91% (95% CI 0.33–42.38%) vs 25.07% (95% CI 12.64–39.65%) respectively.

Figure 2.

Figure 2

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Estimates of ACM, PCSM, and OCM stratified by low or normal testosterone at first PSA failure. (A) 1-Kaplan–Meier estimates of ACM (log-rank P = 0.046). (B) Cumulative incidence estimate of PCSM (Gray’s P <0.0001). (C) Cumulative incidence estimate of OCM (Gray’s P = 0.0504).

DISCUSSION

We observed that men with low testosterone at first PSA failure had less favorable clinical characteristics, including worse survival outcomes, a significantly increased risk of ACM and PCSM and lower risk of OCM compared to men with normal testosterone. Specifically, of the 11 men with low testosterone at first PSA failure, eight died of PC after a median follow-up of only 6.68 years following PSA failure. These observations identify low, but not necessarily castrate, testosterone levels at first PSA failure as a poor prognostic factor following definitive management with RT and combined ADT in men with unfavorable-risk PC.

The clinical significance of these observations is that it provides evidence to support testosterone testing at the time of first PSA failure as an opportunity to identify men who have a more aggressive cancer recurrence and therefore a worse prognosis. Specifically, given a rising PSA in the setting of low testosterone, meaning conventional ADT is extremely unlikely to be effective, future clinical trials in these men are warranted. While docetaxel, enzalutamide and abiraterone are not approved in the non-metastatic castrate-resistant setting, the survival benefit of abiraterone or docetaxel when added to ADT in men with castrate-sensitive metastatic PC10–13 and possibly high-risk localized PC11,13,14 provides rationale to support testing them in combination with conventional ADT in men with low testosterone at first PSA failure. Specifically, in the setting of a phase II trial with ADT and abiraterone, enzalutamide and/or docetaxel, men would be stratified by low or normal testosterone at initial diagnosis. This stratification is supported by prior studies demonstrating that low testosterone at PC diagnosis is associated with poorer prognosis after RP or RT and ADT and shorter responses to salvage ADT15–18. If a high PSA response rate (such as a >80% decline in pretreatment PSA or more stringently achieving an undetectable PSA <0.1 ng/mL) in at least two-thirds of the study cohort is observed, this would provide the basis to support a phase III trial in this setting investigating standard ADT with one or more novel agents and their impact on survival.

Several points require further discussion. First, multiple investigations have shown that post-treatment response factors following RT and ADT such as PSA nadir >0.5 ng/mL, PSA DT <3 months, and interval to PSA failure, are not only prognostic—but also a surrogate for PCSM and/or ACM4,28. However, these investigations were undertaken prior to recent trials demonstrating a survival advantage to abiraterone, docetaxel, and enzalutamide in metastatic castrate-resistant PC, and abiraterone and docetaxel in castrate sensitive metastatic PC7–13. Therefore, whether these post-treatment response factors remain surrogates for ACM in the modern salvage therapy era has yet to be elucidated. Moreover, the post-treatment factor of low testosterone at first PSA failure and both PSA nadir >0.5 ng/mL and PSA DT <3 months could be tested against one another using a metric such as the proportion of treatment effect explained by the proposed surrogate29, to determine which candidate surrogate marker is best and most appropriate to use in future prospective trials.

Second, in the era of advanced molecular imaging for recurrent disease after primary treatment failure—including the FDA-approved (18F-fluciclovine, 11C-choline, 18F-NaF), the non-approved but commonly used (11C-acetate, 68Ga-PSMA) and the early investigational (18F-choline, 18F-FDHT, 18F-DCFBC, 18F-DCFPyL) PET radioligands30—it would be of interest to explore whether men with low versus normal testosterone at first PSA failure have residual or recurrent disease identified using advanced imaging by validating with biopsy. Of note, we observed in the current study that men with low testosterone at PSA failure initiated salvage ADT sooner than men with normal testosterone (Table 1). Whether advanced imaging in this castrate resistant subgroup at first PSA failure can identify site(s) of residual/recurrent disease sooner when compared to standard imaging is worthy of further study.

Finally, potential limitations of this study are the small sample size and its retrospective nature. Therefore, in order to provide further evidence supporting phase II testing of this concept, additional validation in larger datasets with mature follow-up is warranted. However, despite the small sample size, there remains a significant effect of low testosterone at PSA failure as a prognostic factor, as evidence by the increased risk of PCSM (AHR 13.71, 95% CI 2.4–78.16; P=0.003 and see Table 2) in men with low versus normal testosterone. Moreover, as eight of 11 men (72.7%) with low testosterone at PSA failure died of PC as compared to two of the 48 men (4.2%) with normal testosterone, this increased risk of PCSM translated into an increased risk of ACM (AHR, 2.54, 95% CI 1.04–6.21; P=0.04, and see Figure 2A).

CONCLUSIONS

Despite the potential limitations described above, these data demonstrate that men with low, but not necessarily castrate, testosterone levels at first PSA failure have a very poor prognosis. These observations provide evidence to support testosterone testing at PSA failure. Moreover, given that survival is prolonged when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly in men with localized high-risk PC provides rationale to support their use with ADT in men with low testosterone at first PSA failure in the setting of a phase II trial.

Acknowledgments

Grant Support: P30 CA008748

Footnotes

Author contributions: Katelyn Atkins: Conceptualization, methodology, formal analysis, investigation, writing–original draft, writing–review and editing, visualization, project administration. Ming-Hui Chen: Methodology, software, formal analysis, investigation, data-curation, writing–review and editing, visualization, project administration. Jing Wu: Methodology, software, formal analysis, investigation, writing–review and editing. Andrew Renshaw: Methodology, formal analysis, investigation, resources, writing–review and editing. Marian Loffredo: Methodology, investigation, resources, data-curation, writing–review and editing, project administration. Philip Kantoff: Methodology, formal analysis, investigation, resources, writing–review and editing. Eric Small: Methodology, formal analysis, investigation, resources, writing–review and editing. Anthony D’Amico: Conceptualization, methodology, formal analysis, investigation, resources, data-curation, writing–original draft, writing–review and editing, supervision, project administration.

Funding: No specific funding

Conflict of interest disclosures:

Katelyn Atkins, Ming-Hui Chen, Jing Wu, Andrew Renshaw, Marian Loffredo, Anthony V. D’Amico: Nothing to disclose. Philip Kantoff: Stock or Other Ownership: Bellicum Pharmaceuticals, Placon, Druggablity Technologies, Tarveda Therapeutics. Consulting or Advisory Role: Bavarian Nordic, Janssen, Astellas Pharma, Bellicum Pharmaceuticals, BIND Biosciences, Metamark Genetics, Merck, MTG Therapeutics, OncoCellMDX, Oncogenex, Sanofi, Bayer, Genentech/Roche, Ipsen, Omnitura, MorphoSys, GTx, Tarveda Therapeutics, Druggablity Technologies, Progenity, Thermo Fisher Scientific. Research Funding (relationship: institution): Medivation, Sanofi, Oncogenex, Aragon Pharmaceuticals, Amgen, Astellas Pharma, Bayer, Bavarian Nordic, Dendreon, Exelixis, Janssen. Patents, Royalties, Other Intellectual Property: Method for Predicting the Risk of Prostate Cancer Morbidity and Mortality, Predicting and Treating Prostate Cancer, Methods for Predicting Likelihood of Responding to Treatment, Chromosome Copy Number Gain as a Biomarker of Urothelial Carcinoma Lethality, Drug Combinations to Treat Cancer, Somatic ERCC2 Mutations Correlate with Cisplatin sensitivity in muscle-invasive Urothelial Carcinoma (Patent), Up-to-Date Royalties, Wolters Kluwer Royalties, Methods and Kits for Determining Sensitivity to Cancer Treatment, Composition and Methods for Screening and Diagnosis of Prostate Cancer. Expert Testimony: Sanofi, Janssen. Travel, Accommodations, Expenses: Sanofi, Tarveda Therapeutics. Eric Small: Stock or Other Ownership: Fortis Therapeutics, Harpoon Therapeutics. Honoraria: Janssen-Cilag. Consulting or Advisory Role: Fortis Therapeutics, Gilead Sciences, Valeant Pharmaceuticals International. Research Funding: Janssen (relationship: institution).

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