Original Article. Cancer March 1,

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1 Time to Prostate-Specific Antigen Nadir Independently Predicts Overall Survival in Patients Who Have Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen-Deprivation Therapy Toni K. Choueiri, MD, Wanling Xie, MS, Anthony V. D Amico, MD, Robert W. Ross, MD, Jim C. Hu, MD, Mark Pomerantz, MD, Meredith M. Regan, PhD, Mary-Ellen Taplin, MD, Philip W. Kantoff, MD, Oliver Sartor, MD, and William K. Oh, MD BACKGROUND: The objective of this study was to evaluate the relation between the kinetics of prostatespecific antigen (PSA) decline after the initiation of androgen-deprivation therapy (ADT) and overall survival (OS) in men with metastatic, hormone-sensitive prostate cancer (HSPC). METHODS: The authors institutional database was used to identify a cohort of men with metastatic HSPC who were treated with ADT. Patients were included if they had at least 2 serum PSA determinations before PSA nadir and at least 1 serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN), and PSA decline (PSAD) in relation to OS were analyzed. RESULTS: One hundred seventy-nine patients were identified, and they had a median follow-up after ADT initiation of 4 years. The median OS after ADT initiation was 7 years. The median PSA level at ADT initiation and PSA nadir were 47 ng/ml and 0.28 ng/ml, respectively. On univariate analysis: TTN <6 months, PSAD >52 ng/ ml per year, PSA nadir 0.2 ng/ml, PSA 47.2 ng/ml at ADT initiation, and Gleason score >7 were associated with shorter OS. On multivariate analysis, TTN <6 months, Gleason score >7, and PSA nadir 0.2 ng/ ml independently predicted shorter OS. CONCLUSIONS: To the authors knowledge, this was the first report to demonstrate that a faster time to reach a PSA nadir after the initiation of ADT was associated with shorter survival duration in men with metastatic HSPC. These results need confirmation but may indicate that a rapid initial response to ADT indicates more aggressive disease. Cancer 2009;115: VC 2009 American Cancer Society. KEY WORDS: prostate cancer, androgen-deprivation therapy, hormone-sensitive metastatic prostate cancer, prostate-specific antigen kinetics, time to prostate-specific antigen nadir. Corresponding author: Toni K. Choueiri, MD, 44 Binney Street, Dana 1230, Boston, MA 02115; Fax: (617) ; toni_choueiri@dfci.harvard.edu Dana-Farber Cancer Institute/Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts Received: June 10, 2008; Revised: July 20, 2008; Accepted: July 23, 2008 Published online: January 17, 2009, VC 2009 American Cancer Society DOI: /cncr.24064, Cancer March 1,

2 Androgen -deprivation therapy (ADT) is the most effective systemic therapy for patients who have hormonesensitive prostate cancer (HSPC). Most patients will experience a substantial decline in prostate-specific antigen (PSA) levels, and PSA levels may remain low or undetectable for years. Nevertheless, the emergence of castrationresistant prostate cancer (CRPC) is typical. 1 Once CRPC develops, the median survival is approximately 24 to 36 months. PSA kinetics have been established as useful prognostic indicators for survival in different clinical settings. For instance, a high pretherapy PSA velocity (PSAV) is associated with a greater risk of death from prostate cancer despite radical prostatectomy 2 or external beam radiation therapy (EBRT). 3 Similarly, the PSA doubling time with biochemical recurrence after definitive local therapy is able to identify patients who are at high risk of prostate cancer-specific mortality. 4 However, the influence of PSA kinetics post-adt initiation on the outcome of patients with metastatic HSPC is poorly characterized. A recent large study suggested that a PSA level 4 ng/ml after 7 months of ADT is a strong predictor of survival in this population. 5 We queried a longitudinal database of patients who were treated at the Dana-Farber Cancer Institute (DFCI) to describe the outcome of ADT use in men with HSPC who had metastases at the time ADT was initiated. Our objective was to determine which parameters of PSA kinetics predicted overall survival (OS). MATERIALS AND METHODS Database The cohort was generated from the Prostate Clinical Research Information System (CRIS) at DFCI. The CRIS system consists of data entry software, a central data repository, collection of patient data (including comprehensive follow-up of all patients), and tightly integrated security measures. This system recently was described. 6 Data are stored in an Oracle relational database (Oracle, Inc., Redwood Shores, Calif). The current version of Prostate CRIS became available for prospective data entry in November All patients who are seen at DFCI and Brigham and Women s Hospital with a diagnosis of prostate cancer are approached to participate. The consent rate is >85%. In general, patients are followed every 3 months with PSA tests and radiologic examinations if needed. Patient Selection We identified and included patients with prostate cancer who had been treated with ADT (orchiectomy or luteinizing hormone-releasing hormone agonists with or without an antiandrogen) for metastatic HSPC. Patients had consented to provide information on the CRIS protocol and had blood collected for research purposes. Patients were eligible if they had metastatic disease when they started ADT, if they had at least 1 PSA value within 1 month before the initiation of ADT (84.4% of all patients) or after ADT initiation (15.6% of all patients), and if they had at least 2 PSA values available before nadir PSA (including nadir PSA). Patients were excluded either if they had only 2 PSA values available and the second value was obtained >1 year after the first measure or if their PSA level increased after ADT initiation. Statistical Considerations Patient and disease characteristics were summarized as the number (%) of patients or the median and range of values. The time to PSA nadir (TTN) was defined as the duration of time from the initiation of ADT to the date the lowest PSA value first was observed after ADT. PSA decline (PSAD) was calculated from the slope of the linear regression of the raw PSA values over time using PSA values from 1 month before ADT to the nadir PSA. The primary outcome variable was OS, which was defined as the time from ADT initiation to the date of death, and patients were censored at the last known date that they were alive. The distribution of OS was estimated using the Kaplan-Meier product-limit method; median survival and OS along with 95% confidence intervals (CIs) were summarized. OS was compared according to patients characteristics using log-rank tests. Continuous variables were dichotomized at the median value within the cohort with the exception of PSA nadir, which was dichotomized at 0.2 ng/ml because of its known correlation with prostate cancer-specific survival. Because PSA nadir, TTN, and PSAD were measures that developed over time after ADT initiation, we also conducted secondary analyses of OS from the landmarks of PSA nadir on 982 Cancer March 1, 2009

3 PSA Nadir Predicts HSPC Survival/Choueiri et al Table 1. Patient and Disease Characteristics of the Metastatic Hormone-Sensitive Prostate Cancer Cohort at the Initiation of Androgen-Deprivation Therapy (N¼179) Characteristic No. of Patients (%) Median IQR At diagnosis Clinical T3 tumor 10 (5.6) Clinical M1 status 58 (32.4) Clinical N1 status 25 (14) Biopsy Gleason >7 84 (46.9) Definitive local therapy (RP or RT) 85 (47.5) Hormone therapy for local disease 21 (11.7) At ADT initiation Age, y Time from diagnosis to ADT, y PSA at ADT initiation, ng/ml Orchiectomy 1/2 LHRH analog 11 (6.1) Intermittent LHRH 5 (2.9) LHRH and antiandrogen 144 (80.4) During ADT Nadir PSA during ADT, ng/ml Time to PSA nadir, mo PSAD after ADT, ng/ml/y IQR indicates interquartile range; T, tumor classification; M, metastasis classification; N, lymph node status; RP, radical prostatectomy; RT, radiotherapy; ADT, androgen-deprivation therapy; PSA, prostate-specific antigen; þ/, with or without; LHRH: luteinizing hormone-releasing hormone; PSAD: PSA decline. ADT (postnadir OS) and 1 year after ADT initiation. Multivariate modeling was undertaken to arrive at a parsimonious model to predict OS; hazard ratios (HRs), 95% CIs, and Wald chi-square test P values were reported from the models. The statistical analysis was undertaken using SAS software (version 9; SAS Institute Inc., Cary, NC) and P values <.05 (2-sided) were considered statistically significant. RESULTS Patient Characteristics and Prostate-Specific Antigen Kinetics One-hundred seventy-nine patients met the eligibility criteria for this analysis (Table 1). The median age of the cohort at ADT initiation was 64 years (range, years). Forty-seven percent of patients had a Gleason score >7, and 32% of patients had metastatic disease (M1) at diagnosis. The median time from diagnosis to the initiation of ADT was 0.3 years (interquartile range [IQR], years). Eighty percent of patients received an antiandrogen as part of ADT. The median PSA level at ADT initiation was 47 ng/ml, and the median PSA nadir was 0.28 ng/ml; 45% of patients reached a PSA nadir <0.2 ng/ ml. The median TTN was 6 months, and the median PSAD level after the initiation of ADT was 52 ng/ml per year. The PSA levels at the start of ADT were similar between the groups with short (<6 months) and prolonged (6 months) TTN (median, 31 ng/ml vs 55.6 ng/ml; P ¼.21). However, the group with rapid PSAD (>52 ng/ml per year) had much higher baseline PSA levels compared with the group with slow PSAD (median, 146 ng/ml vs 12.5 ng/ml; P <.0001). Patients who had a rapid PSAD or shorter TTN also were less likely to achieve a PSA nadir <0.2 ng/ml (P <.05). Univariate and Multivariate Analyses of Predictors for Overall Survival With a median follow-up of 4 years (range, years), 63 patients (35%) patients died. The median OS after ADT initiation was 7 years (95% CI, years; range, years). Table 2 summarizes survival estimates at 1-year intervals after the initiation of ADT. Several factors were identified that predicted OS after the initiation of ADT on univariate analysis (Table 3). Cancer March 1,

4 A Gleason score >7, higher PSA at the initiation of ADT, higher PSA nadir, shorter TTN, and a more rapid PSAD all were associated with a shorter OS. Figure 1 provides OS curves that were calculated according to TTN (<6 months vs 6 months; log-rank P ¼.01) and PSAD (<52 ng/ml per year vs 52 ng/ml per year; log-rank P ¼.0012). Secondary landmark analyses that compared postnadir survival among patient groups defined by these variables or that compared survival for those who had been alive for at least 1 year after ADT initiation were Table 2. Kaplan-Meier Estimates of Overall Survival at Yearly Intervals After the Initiation of Androgen Deprivation Therapy Time After ADT, y OS Rate, % 95% CI, % ADT indicatess androgen-deprivation therapy; OS, overall survival; CI, confidence interval. consistent with our initial results. It is noteworthy that previous local therapy (radiotherapy or radical prostatectomy) was associated with OS on univariate analysis (P ¼.009) but not on multivariate analysis (P ¼.98). In multivariate analysis, statistically significant predictors for OS were PSA nadir, TTN, and Gleason score. Higher PSA nadir (0.2 ng/ml), shorter TTN (<6 months), and higher Gleason (>7) were associated with shorter survival (Table 4, Model 1). We also investigated whether the association of TTN with OS was modified by the levels of PSA nadir (Table 4, Model 2). The results indicated that the relation between prolonged TTN and improved survival became more apparent in patients who had a PSA nadir 0.2 ng/ml (hazard ratio [HR], 0.31; 95% CI, ). However, in the group of patients who had a PSA nadir <0.2 ng/ml, TTN had no influence on survival (HR, 1.0; 95% CI, ; interaction effect, P ¼.04). A Kaplan-Meier plot of survival by PSA nadir and TTN (Fig. 2) indicated that the 2 survival distributions (TTN 6 months vs TTN <6 months) crossed, and there was a lot of early censoring among patients who had a PSA nadir <0.2 ng/ml, which Table 3. Univariate Analysis of Factors That Predicted Overall Survival From the Initiation of Androgen-Deprivation Therapy and From Alternative Landmark Time Points OS after ADT, N5179 OS in Patients Who Were Alive >1 Year After ADT, N5159 Postnadir OS, N5179 Variable Median, y P Median, y P Median, y P All patients 7.0 Biopsy Gleason >7 5.2 Unknown 3.8 PSA at ADT initiation, ng/ml < PSA nadir, ng/ml < < < < TTN, mo < PSAD, ng/ml/y > OS indicates overall survival; ADT, androgen-deprivation therapy; PSA, prostate-specific antigen; TTN, time to PSA nadir; PSAD, PSA decline. 984 Cancer March 1, 2009

5 PSA Nadir Predicts HSPC Survival/Choueiri et al suggested that the association between survival and TTN remained unclear in patients who achieved a very low nadir in this cohort. The results were consistent when variables were analyzed on a continuous basis rather than dichotomized (data not shown). FIGURE 1. Overall survival from the initiation of androgendeprivation therapy (ADT) according to prostate-specific antigen (PSA) decline (PSAD) (top) and the time to PSA nadir (TTN) (bottom). DISCUSSION In 2007, the American Society of Clinical Oncology published clinical practice guidelines on the initial hormone management of androgen-sensitive, metastatic prostate cancer. 7 ADT remains the mainstay of treatment for men with metastatic HSPC. PSA kinetics before definitive curative-intent therapy and during biochemical recurrence when these therapies fail are established prognostic factors associated with outcome. 2,3,8 Petrylak et al observed that a decline in PSA velocity after beginning treatment with docetaxel chemotherapy, were associated with OS. 9 An analysis from the TAX327 trial of docetaxel versus mitoxantrone in metastatic, hormone-refractory prostate cancer 10 demonstrated that a PSAD 30% within 3 months of initiating chemotherapy had the highest degree of surrogacy for OS, confirming data from the Southwest Oncology Group 9916 trial. By using data from a randomized phase 3 trial, Hussain et al recently reported that a PSA value 4ng/mL after 7 months of ADT was a strong independent predictor of improved survival in new, metastatic HSPC. 5 Table 4. Multivariate Models Predicting Overall Survival Variable HR 95% CI P Model 1: Main effects only Biopsy Gleason (>7vs 7) Biopsy Gleason (unknown vs 7) PSA nadir ( 0.2 ng/ml vs <0.2 ng/ml) <.0001 TTN ( 6 movs <6 mo) Model 2: Investigating interaction Biopsy Gleason (>7vs 7) Biopsy Gleason (unknown vs 7) Nadir <0.2 ng/ml TTN <6mo 1.00 (Reference) TTN 6mo * Nadir 0.2 ng/ml TTN <6mo 1.00 (Reference) TTN 6mo HR indicates hazard ratio; CI, confidence interval; TTN, time to prostate-specific antigen (PSA). *The Wald chi-square test was used to test the interaction between nadir PSA and TTN. Cancer March 1,

6 FIGURE 2. Overall survival according to the nadir prostatespecific antigen (PSA) and the time to PSA nadir (TTN). Those results may allow the identification of patients who are unlikely to benefit with standard ADT long before they develop castration-resistant disease, thus providing an alternative to investigating newer therapies. Unfortunately, the influence of PSA kinetics like PSAD, TTN, and others as predictors of survival in patients with metastatic but HSPC remains largely unknown. Most studies have evaluated PSA responses 5,11,12 as a surrogate for survival. Overall, the efficacy of ADT has been correlated with more profound PSADs that reflect subsequently improved survival. In our dataset, a lower PSA nadir, as expected, was associated independently with longer survival. We also attempted to examine other parameters of PSA kinetics to refine the predictive information in this context. It is noteworthy that a more rapid PSAD and a shorter TTN (a cutoff of 6 months was used for convenience, because this was the median value) were associated with shorter survival, and TTN was associated independently with survival even after adjusting for several other variables. We believed that it was reasonable to assume that a rapid PSAD and reaching PSA nadir faster would indicate more cancer cell death that, subsequently, would translate into a higher survival, similar to the data regarding docetaxel chemotherapy in hormone-refractory disease. 9 Because of our findings, we hypothesize that perhaps this is an ADT-specific phenomenon only; the rapid fall in PSA may not be related to cell viability and simply may be a transcriptional effect from ADT on PSA production rather than cell death. Another possible explanation is that we may have selected a subset of aggressive prostate cancer cells that quickly became resistant to ADT or were not as reliant on the androgen receptor for viability. In fact, significant clinical heterogeneity may exist in metastatic HSPC, as supported by the data of Hussain et al, who observed a striking variability in survival: Patients in their study had median survival differences that ranged from 13 months to 75 months, depending on the absolute PSA nadir achieved. In the current study, the association between TTN and survival was limited only to patients who had a PSA nadir >0.2 ng/ml. We also attempted to examine the length of time from the initiation of ADT to the first documentation of a PSA level 0.2 ng/ml, because some investigators equate a PSA level 0.2 ng/ml with an undetectable PSA, especially with less sensitive PSA assays. By using this alternative definition, the results were not different for patients who did not achieve a PSA nadir 0.2 ng/ml. However, there was no association between TTN and survival for those who were able to achieve a PSA nadir 0.2 ng/ml after ADT. The relation between TTN and survival deserves further investigation in patients with a lower PSA nadir. Rapid PSAD predicted a worse survival in the univariate analysis but did not retain its importance in the multivariate models when we included Gleason score, PSA nadir, and TTN. We also observed a strong association between PSAD and PSA at the start of ADT. Although the variability in PSA was relatively large (range, 0-15,090 ng/ml; IQR, ng/ml) at the initiation of ADT, nearly 75% of patients in this cohort achieved a PSA level 3 ng/ml within 6 months of ADT. Therefore, the rate of PSAD was determined primarily by the PSA level at ADT initiation. To our knowledge, our findings have not been reported previously in studies of ADT. This report is the first to use PSA kinetics (such as TTN) outcome measure to evaluate ADT efficacy in metastatic HSPC. This analysis has some potential pitfalls. First, it is retrospective. The measurements of PSA kinetics will depend on the number and the pattern of PSA testing post-adt initiation. The quality of the data, however, should be high, because we performed a quality-control analysis and observed the numbers of available PSA values at 6 months of ADT were similar between the groups with shorter and longer 986 Cancer March 1, 2009

7 PSA Nadir Predicts HSPC Survival/Choueiri et al TTN. Second, although all patients had metastatic HSPC, this analysis also drew on patients with heterogeneous clinical backgrounds that were not controlled for in the context of a prospective clinical trial. Some important factors, such as lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and hemoglobin, were not included in this analysis, because they are not measured routinely in patients who receive ADT at our institution. Finally, we did not study patients who never received ADT or those who received antiandrogens alone; however, we believe that those patients represent rare case scenarios. To summarize, we observed that PSA kinetics at the initiation of ADT could predict OS in patients with metastatic HSPC and that faster TTN and more rapid PSAD were associated with a shorter OS. We postulate that this may be a consequence of underlying biologic differences in tumor heterogeneity. Further prospective data and external validation in independent datasets are needed to confirm these finding. Conflict of Interest Disclosures Supported by the Gelb Center for Translational Research (P.W.K., W.K.O.), the Bing Sound Wong Fund for Prostate Cancer Research (W.K.O.), and the Dana Farber/Harvard Cancer Center Prostate Cancer Specialized Program of Research Excellence (NCI 5P50CA90381). References 1. Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol. 2007;4: D Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351: D Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA. 2005;294: Zhou P, Chen MH, McLeod D, Carroll PR, Moul JW, D Amico AV. Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Clin Oncol. 2005;23: Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006;24: Oh WK, Hayes J, Evan C, et al. Development of an integrated prostate cancer research information system. Clin Genitourin Cancer. 2006;5: Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25: D Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280: Petrylak DP, Ankerst DP, Jiang CS, et al. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG J Natl Cancer Inst. 2006;98: Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al. Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol. 2007;25: Collette L, Burzykowski T, Carroll KJ, Newling D, Morris T, Schroder FH. Is prostate-specific antigen a valid surrogate endpoint for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol. 2005;23: Oosterlinck W, Mattelaer J, Casselman J, Van Velthoven R, Derde MP, Kaufman L. PSA evolution: a prognostic factor during treatment of advanced prostatic carcinoma with total androgen blockade. Data from a Belgian multicentric study of 546 patients. Acta Urol Belg. 1997;65: Cancer March 1,