- Email: [email protected]
Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment
Original Study
Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment Rahul Aggarwal,1 Anna Harris,1 Carl Formaker,1 Eric J. Small,1 Arturo Molina,2 Thomas W. Griffin,3 Charles J. Ryan1 Abstract In this study, clinical outcomes after docetaxel therapy in 23 patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with abiraterone acetate (AA) were retrospectively evaluated. Subsequent docetaxel therapy led to ‡ 50% prostate-specific antigen (PSA) decline in 11 patients (48%) of patients; this outcome was not affected by pattern of AA resistance. The PSA response rates suggest that docetaxel and AA are not cross-resistant; however, further prospective study is required. Introduction/Background: Docetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies. Patients and Methods: Patients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed. Results: We identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to 30% PSA decline in 15 patients (65%) and 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy. Conclusion: In this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Androgen signaling, Cross-resistance, Chemotherapy, PSA response, Subsequent therapy
Introduction Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of the disease, and accounts for more than 29,000 deaths 1 Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 2 Janssen Research & Development, Menlo Park, CA 3 Janssen Research & Development, Los Angeles, CA
Submitted: Feb 6, 2014; Revised: Mar 10, 2014; Accepted: Mar 11, 2014 Address for correspondence: Rahul Aggarwal, MD, 1600 Divisadero St B745, San Francisco, CA 94143 Fax: 415-353-7093; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.010
annually in the United States.1 Within the past decade, multiple new therapeutic modalities have produced declines in serum prostatespecific antigen (PSA) and objective tumor responses, lengthened overall survival, and palliated symptoms in patients with mCRPC. Such therapies include taxane-based chemotherapy, radiopharmaceuticals, immunotherapy, androgen synthesis inhibitors such as abiraterone acetate (AA), and potent androgen receptor (AR) antagonists, including enzalutamide.2-8 In current clinical practice, patients are often treated sequentially with single-agent therapy until the time of disease progression or cumulative toxicity. Several key questions have emerged within the paradigm of sequential therapy for mCRPC: (1) Is there an optimal sequence of therapy?
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Outcomes With Docetaxel After Abiraterone in mCRPC (2) Does previous therapy with one therapeutic modality result in cross-resistance to other modalities? (3) Can subcategorizing patients on the basis of previous patterns of treatment resistance have predictive utility to help guide the choice of subsequent treatment? It is not known whether previous therapy with an androgen synthesis inhibitor results in cross-resistance to therapy with antitubule agents, such as docetaxel. If cross-resistance exists between these modalities of therapy, primary resistance to androgen synthesis inhibitors might be predictive of refractoriness to subsequent treatment with docetaxel. Some retrospective studies have suggested the potential for cross-resistance between androgen synthesis inhibitors, including ketoconazole and AA, and subsequent taxane-based chemotherapy,9 and others have failed to demonstrate compelling evidence for cross-resistance.10 In one retrospective study, AA-refractory patients were defined as those without PSA decline > 50% from baseline.9 In this subgroup of AA-refractory patients, no patients had a decline in PSA with subsequent docetaxel therapy.9 Taxane-mediated inhibition of AR nuclear transport and ARmediated gene transcription might provide the mechanistic link for potential cross-resistance with androgen signaling inhibition.11,12 It is hypothesized that previous therapy with potent inhibitors of the androgen signaling pathway, including AA, might lead to the emergence of treatment-resistant subclones of cancer cells that are less “androgen responsive” and thus less likely to respond to subsequent docetaxel chemotherapy. The objective of the current study was to evaluate potential crossresistance between androgen synthesis inhibitors and taxane-based chemotherapy. In this retrospective analysis of an independent cohort of patients with mCRPC who had disease progression with AA therapy, we examined disease outcomes with subsequent treatment with docetaxel. For this analysis, patients with radiographic stability for at least 8 months or PSA decline 50% from baseline were considered to have acquired resistance, and all others to have primary AA resistance. The cutoff for radiographic disease stability of at least 8 months was chosen because this was the observed approximate median radiographic progression-free survival in the prednisone with placebo control arm in the phase III study of AA in chemotherapy-naive mCRPC.5
Methods
The timing and choice of therapy after AA, and methods of response assessment, were per the discretion of the treating physician. Docetaxel schedules included weekly regimens (35 mg/m2 weekly; n ¼ 2) or every-3-week dosing (ranging from 60 to 75 mg/m2 every 3 weeks; n ¼ 21), all with concomitant prednisone. Patients who were concurrently treated with carboplatin or investigational therapies in addition to docetaxel were not included in this analysis. The duration of docetaxel therapy was per individual treating physician. Reasons for treatment discontinuation were assessed retrospectively. Each patient had signed an institutional review board (IRB)approved, protocol-specific informed consent form in accordance with federal and institutional guidelines before initiating treatment with AA. The subsequent retrospective review of outcomes after docetaxel therapy was IRB-approved.
Statistical Methods and Data Analysis Retrospective data collected included baseline patient characteristics at the start of docetaxel therapy such as validated prognostic factors in mCRPC, baseline PSA, Gleason score at the time of diagnosis, presence of visceral metastases, and use of opioid analgesics for cancer-associated pain.16 The maximal PSA percent decline from baseline was determined using all known serum PSA determinations obtained during therapy. Patients were categorized as experiencing PSA declines 30% and 50% from baseline if confirmed using repeat PSA measurement at least 4 weeks after the initial measurement, consistent with PCWG2 guidelines.15 The Kaplan-Meier product limit method was used to estimate the median overall survival from the date of first dose of docetaxel.17 Patients were censored at the date last known alive for the analysis of overall survival. Patients were subdivided into those with primary versus acquired AA resistance. Acquired AA resistance was defined as patients who experienced a PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression with AA. All other patients were defined as having primary AA resistance. Outcomes after docetaxel therapy according to subgroups of patients with primary or acquired resistance to AA were assessed using descriptive statistics. No formal statistical comparisons were performed between subgroups.
Study Population and AA Treatment Schedule
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Patients with mCRPC who were treated with AA until the time of disease progression in phase I/II (NCT00473746) and III (NCT00887198) clinical trials and had available data on outcomes with subsequent docetaxel chemotherapy were included in this retrospective, single-institution analysis. The eligibility criteria for the clinical trials of AA have been reported.5,13 Patients were chemotherapy-naive and had metastatic prostate cancer with disease progression despite castrate levels of serum testosterone (< 50 ng/dL). In the phase I study, the dose of AA ranged from 250 to 1000 mg/d, with or without concomitant prednisone. In the phase II and III studies, patients received standard dosing (AA 1000 mg/d in modified fasting state concomitantly with prednisone 5 mg orally twice daily). Patients were treated with AA until the time of disease progression according to Prostate Cancer Working Group (PCWG) or PCWG2 criteria,14,15 unacceptable toxicity, or study withdrawal.
Clinical Genitourinary Cancer Month 2014
Results Outcomes With Previous AA Therapy and Baseline Patient Characteristics Twenty-three patients who experienced disease progression while taking AA and were subsequently treated with docetaxel between 2007 and 2013 were included in this retrospective analysis, including 11 (48%) treated with AA in the phase III randomized study (subsequent unblinding of phase III treatment allocation allowed identification of patients with previous AA therapy). The distribution of AA dosing is shown in Table 1. Fifteen patients (65%) were treated at the standard dosing of AA (1000 mg/d in a modified fasting state with prednisone 5 mg twice daily). Outcomes for AA therapy are shown in Table 1. Twelve patients (52%) experienced a 50% decline from baseline in serum PSA with AA treatment. Fifteen patients (65%) discontinued AA because of radiographic or clinical progression and 8 (35%) because of PSA progression; the median
Rahul Aggarwal et al Table 1 Outcomes With Previous AA Therapy and Baseline Characteristics at the Start of Docetaxel Treatment Characteristic
Patient cohort (n [ 23)
Outcomes With Previous AA Therapy Dose and administration of previous AA therapy, n (%) 250 mg/d
1 (4)
500 mg/d
3 (13)
750 mg/d
2 (9)
1000 mg/d
17 (74)
With prednisone
15 (65)
Without prednisone
8 (35)
Maximal PSA decline 50% from baseline during previous AA therapy, n (%)
12 (52)
Median duration of previous AA therapy, months (range)
7.4 (2.2-43.0)
Reason for AA discontinuation, n (%) PSA PD Radiographic or clinical PD Median duration from AA discontinuation to docetaxel treatment initiation, months (range)
8 (35) 15 (65) 2.7 (0.2-14.7)
Intervening therapies between AA discontinuation and docetaxel treatment initiation, n (%) Any
8 (35)
Ketoconazole
6 (26)
Nilutamide
1 (4)
Diethylstilbestrol
1 (4)
Baseline Characteristics at the Start of Docetaxel Treatment Median age, years
67
Gleason grade at time of diagnosis, n (%) 6 7 8 Median baseline PSA, ng/mL (range)
2 (9) 4 (17) 17 (74) 260 (19-15,190)
Opioid analgesic use, n (%)
15 (65)
Visceral metastases, n (%)
2 (9)
Abbreviations: AA ¼ abiraterone acetate; PD ¼ progressive disease; PSA ¼ prostate-specific antigen.
duration of AA therapy was 7.4 months (range, 2.2-43.0 months). Eight patients (35%) received intervening therapies between AA treatment discontinuation and initiation of docetaxel, most of whom (n ¼ 6) received ketoconazole. Baseline patient characteristics at the start of subsequent docetaxel chemotherapy are shown in Table 1. The median duration between AA discontinuation and first dose of docetaxel chemotherapy was 2.7 months (range, 0.2-14.7 months). Most patients (n ¼ 15; 65%) required opioid analgesics for bone metastasisassociated pain at the start of docetaxel, and the median baseline serum PSA was 260 ng/mL (range, 19-15,190 ng/mL).
Outcomes With Docetaxel Therapy After Previous AA Therapy Clinical outcomes with docetaxel therapy after previous AA therapy are shown in Table 2. Fifteen patients (65%) experienced 30%
PSA decline from baseline, and 11 patients (48%) had 50% maximal PSA decline (Fig. 1). Seven patients (30%) discontinued docetaxel as a result of either adverse events or a break from chemotherapy in the absence of disease progression. The median duration of docetaxel therapy was 4.3 months (range, 2.1-9.8 months). The median overall survival from date of first dose of docetaxel was 12.4 months (95% confidence interval [CI], 8.219.6), with death events observed in 21 of 23 patients. From the start of AA treatment, the median overall survival was 27.2 months (95% CI, 23.6-35.3). The treatment interval between completion of AA and initiation of docetaxel did not appear to influence subsequent outcomes with docetaxel treatment. Dichotomizing the patient cohort into subgroups greater and less than the median interval of 2.7 months between AA discontinuation and docetaxel initiation, the 50% PSA response rate with docetaxel treatment and median overall survival from start of docetaxel were similar between the 2 subgroups (45% and 50%; 12.1 and 12.7 months, respectively).
Outcomes in Subgroups of Patients With Primary and Secondary Resistance to Previous AA Therapy Patients were subdivided into those with primary (n ¼ 9) or acquired (n ¼ 14) resistance to AA using definitions outlined in the Patients and Methods section. The baseline patient characteristics were similar in the 2 cohorts (data not shown). The clinical outcomes are shown in Table 2. The probability of 30% and 50% PSA decline from baseline during docetaxel therapy was numerically similar between subgroups, as was the median duration of docetaxel therapy. Likewise, despite a longer median overall survival from the start of AA in the subgroup of patients with acquired AA resistance (35.3 and 24.8 months, respectively, in acquired and primary AAresistant subgroups), the median overall survival from the start of subsequent docetaxel therapy was similar between the 2 subgroups (12.4 and 12.2 months, respectively) (Fig. 2). The dose level of AA did not appear to affect the patterns of AA resistance or subsequent outcomes with docetaxel treatment. Of the 15 patients who received standard AA dosing (1000 mg/d with prednisone), 6 (40%) had primary resistance to AA and the median overall survival from start of subsequent docetaxel treatment was 12.1 months. Of the 8 patients who received nonstandard AA dosing (< 1000 mg/d with or without concomitant prednisone), 3 (37.5%) had primary resistance to AA and the median duration of overall survival from start of docetaxel was 12.6 months. An alternate definition of primary versus acquired resistance was evaluated in which patients who did not experience any serum PSA decline with previous AA treatment were classified as having mCRPC with primary AA resistance (n ¼ 5); all others were classified as having acquired AA resistance (n ¼ 18). The use of alternate definitions of primary and acquired AA resistance yielded a similar pattern of results. Patients with primary AA resistance using this alternate definition had a shorter median survival from start of AA treatment compared with acquired AA-resistant patients (24.7 months and 34.3 months, respectively), but similar probabilities of PSA decline from baseline during docetaxel treatment (PSA decline 30% in 3 of 5 [60%] and 11 of 18 [61%] patients, respectively) and similar median overall survival from the start of docetaxel therapy (13.1 months and 11.9 months, respectively).
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Outcomes With Docetaxel After Abiraterone in mCRPC Table 2 Outcomes With Docetaxel Therapy According to Pattern of Previous Treatment Resistance to Abiraterone
Characteristic
Overall Patient Cohort (n [ 23)
Previous Primary AA Resistancea (n [ 9)
Previous Acquired AA Resistancea (n [ 14)
Starting Docetaxel Dose, n (%) 35 mg/m2 weekly
3 (13)
2 (22)
60 mg/m every 3 weeks
3 (13)
2 (22)
1 (7)
75 mg/m2 every 3 weeks
17 (74)
5 (56)
12 (86)
2
1 (7)
Maximal PSA Decline ‡ 30%, n (%)
15 (65)
6 (67)
9 (64)
Maximal PSA Decline ‡ 50%, n (%)
11 (48)
4 (44)
7 (50)
Reason for treatment discontinuation, n (%) PSA PD
9 (39)
6 (67)
3 (21)
Radiographic or clinical PD
5 (22)
2 (22)
3 (21)
Adverse event
3 (13)
1 (11)
2 (14)
Treatment break
4 (17)
0
4 (17)
Death
2 (9)
0
2 (14)
Median Duration of Docetaxel , months (range)
4.3 (2.1-9.8)
4.3 (2.1-9.5)
4.6 (2.6-9.8)
Follow-Up Treatments Received After Discontinuation of Docetaxel, n% Any
8 (35)
3 (33)
5 (36)
Cabazitaxel
3 (13)
1 (11)
2 (14)
Carboplatin
3 (13)
1 (11)
2 (14)
Enzalutamide
1 (4)
Radium-223
1 (4)
0
1 (7)
1 (11)
0
Median Overall Survival From First Dose of Docetaxel, Months (95% CI)
12.4 (8.2-19.6)
12.2 (6.6-19.6)
12.4 (7.0-22.5)
Median Overall Survival From First Dose of AA, Months (95% CI)
27.2 (23.6-35.3)
24.8 (11.1-30.6)
35.3 (21.7-38.4)
Abbreviations: AA ¼ abiraterone acetate; PD ¼ progressive disease; PSA ¼ prostate-specific antigen. a Acquired AA resistance was defined as patients who experienced a PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression using AA. All other patients were defined as having primary AA resistance.
Discussion
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The results of the current retrospective analysis suggest a lack of cross-resistance between previous AA treatment and subsequent docetaxel chemotherapy in patients with mCRPC. Nearly half of the patients experienced a 50% PSA decline from baseline during docetaxel treatment. There appeared to be no discernible association between outcomes with AA treatment and subsequent response to docetaxel. Patients with previous primary AA resistance had PSA response proportions and median overall survival from the start of docetaxel similar to patients with previous acquired resistance to AA. Although the definitions of primary and acquired AA resistance are arbitrarily defined in this analysis, PSA and radiographic criteria were used, consistent with PCWG2 guidelines.15 The observation that the median overall survival from start of AA therapy appeared to be shorter in patients with primary versus acquired resistance to AA adds validity to the definition of AA resistance used in this analysis. The use of an alternative definition of primary resistance to AA, defined as no PSA decline during AA therapy, also yielded similar outcomes with docetaxel for those with primary versus acquired AA resistance. The potential for cross-resistance between androgen synthesis inhibitors and docetaxel-based chemotherapy has been assessed preliminarily in several other retrospective studies. An analysis of the effect of the older-generation androgen synthesis inhibitor, ketoconazole, on subsequent outcomes in docetaxel-based chemotherapy
Clinical Genitourinary Cancer Month 2014
in a randomized phase III clinical trial found no differences in outcomes with respect to overall survival, progression-free survival, objective response rates, or PSA declines among those with and without previous ketoconazole exposure.18 That study had the
Figure 1 Maximal PSA Decline From Baseline During Subsequent Docetaxel Treatment According to Primary Versus Acquired Resistance to Previous Treatment With AA
Abbreviations: AA ¼ abiraterone acetate; PSA ¼ prostate-specific antigen.
Rahul Aggarwal et al Figure 2 Kaplan-Meier Curve of Overall Survival From (A) Date of First Docetaxel and (B) Start of Treatment AA for Patients With Primary or Acquired Resistance to AA
Abbreviation: AA ¼ abiraterone acetate.
limitation of using ketoconazole, a less potent and selective androgen synthesis inhibitor than AA, but did assess outcomes with subsequent docetaxel therapy within the framework of a large, cooperative-group, randomized, prospective study. In a separate single-institution retrospective analysis of 35 patients who received docetaxel after AA, only nine patients (26%) experienced 50% decline from baseline in PSA.9 Furthermore, in this analysis, patients with primary AA resistance, defined as those without a > 50% PSA decline from baseline, did not have a subsequent response to docetaxel, which led to the authors’ conclusion of evidence of cross-resistance because of a partial shared mechanism of action between androgen synthesis inhibitors and taxane-based chemotherapy.9 The baseline characteristics of patients in this study were comparable to those included in the current analysis with respect to age and sites of disease. In our study, the patient cohort was more likely to have pain requiring opioid analgesics, and a larger proportion had Gleason grade 8 disease at the time of diagnosis. In the current study, it is noteworthy that the median overall survival of 12.4 months from the start of docetaxel treatment was numerically shorter than the median survival of 18.9 months with every-3-week docetaxel treatment observed in the previous registrational phase III study (TAX327).7 Furthermore, the median duration of docetaxel therapy (4.3 months) was shorter than in the previous phase III study (7.1 months).7 This might potentially reflect true cross-resistance between previous AA and subsequent
docetaxel treatment with respect to overall survival. Alternatively, the observed duration of docetaxel treatment and overall survival might reflect a patient cohort with more adverse disease features at the start of chemotherapy, including a greater median baseline PSA, a greater median Gleason grade, and a greater proportion of patients requiring opioid analgesics compared with the phase III docetaxel trial population,7 and a shorter duration of AA treatment and median survival from start of AA treatment compared with the phase III trial of AA in chemotherapy-naive patients.5 Furthermore, the current study cohort received a greater number of previous systemic therapies for mCRPC compared with the TAX327 study cohort, and this might also influence prognosis in the absence of a specific effect on outcomes with docetaxel. Using a validated prognostic nomogram in mCRPC,16 the predicted median overall survival from the start of docetaxel was 6 months in the current study cohort, further reflecting a patient population with higher-risk disease compared with previous studies with docetaxel-based chemotherapy in mCRPC. Clear limitations of the current study include a small sample size and retrospective design, with possibility of selection bias; variability with respect to the lower dose of AA used in patients treated in the phase I study; and variability in the time interval between discontinuation of androgen synthesis inhibitors and initiation of subsequent therapy. Furthermore, the median duration of AA therapy in the current study cohort (7.4 months) was shorter than in the phase III studies of abiraterone,5 and 8 patients (35%) discontinued AA for PSA-only progression. These factors might influence the degree of “androgen responsiveness” and sensitivity to subsequent taxanebased chemotherapy. Ultimately, the current study results highlight the need for prospective studies to assess for an effect of previous therapy targeting the androgen signaling axis on subsequent outcomes with taxanebased chemotherapy for men with advanced prostate cancer.
Conclusion The results of the current study suggest that patients with acquired or primary resistance to previous treatment with AA have similar PSA response rates and overall survival with subsequent docetaxel treatment in mCRPC. The observed PSA response rates suggest that there is no cross-resistance between these modalities, but prospective data are required to validate definitions of primary versus acquired resistance to androgen-targeting agents in mCRPC and to address the potential for cross-resistance with taxane-based chemotherapy.
Clinical Practice Points Several new therapies for patients with mCRPC have improved
clinical outcomes, including reducing serum PSA, objective tumor responses, and improved overall survival. These therapies include taxane-based chemotherapy, androgen synthesis inhibitors, AR antagonists, immunotherapies, and radiopharmaceuticals. The optimal sequence of therapies for mCRPC is increasingly relevant and remains poorly understood. One retrospective study has reported cross-resistance between androgen synthesis inhibitors, ketoconazole, and AA, and subsequent taxane-based chemotherapy, and another study did not confirm this hypothesis. In this study we retrospectively evaluated this potential crossresistance between AA and subsequent docetaxel in an independent
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Outcomes With Docetaxel After Abiraterone in mCRPC cohort of 23 patients with mCRPC who had disease progression with AA therapy and were subsequently treated with docetaxel. Almost half of patients had a 50% PSA decline from baseline during docetaxel treatment; there was no discernible association between outcomes with AA and subsequent response to docetaxel. Patients with acquired AA resistance (PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression during AA treatment) versus primary AA resistance (all other patients) were also evaluated. Patients with primary AA resistance and acquired AA resistance had similar PSA response and median overall survival from the start of docetaxel treatment. These results suggest a lack of cross-resistance between these modalities, but further prospective evaluation is needed to understand cross-resistance with taxane-based chemotherapy and better define primary versus acquired resistance to androgentargeting agents in mCRPC.
Acknowledgments Writing assistance was provided by Hajira Koeller, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC.
Disclosure Arturo Molina and Thomas W. Griffin are employees of Janssen Research & Development and own stock in Johnson & Johnson. Charles J. Ryan has received honoraria from Janssen. The remaining authors have stated that they have no conflicts of interest.
References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10-29. 2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364:1995-2005.
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3. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13:983-92. 4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369:213-23. 5. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy [published erratum appears in: N Engl J Med 2013; 368:584]. N Engl J Med 2013; 368:138-48. 6. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187-97. 7. Tannock IF, de WR, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351:1502-12. 8. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-22. 9. Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23:2943-7. 10. Aggarwal R, Halabi S, Kelly WK, et al. The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance). Cancer 2013; 119: 3636-43. 11. Van Soest RJ, Van Royen ME, de Morree ES. Effects on androgen receptor nuclear import by docetaxel, cabazitaxel, abiraterone, and enzalutamide: potential mechanism for cross-resistance in castration-resistant prostate cancer (CRPC). J Clin Oncol 2013; 31(suppl) (abstract 5064). 12. Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res 2010; 70:7992-8002. 13. Ryan CJ, Harzstark A, Lin AM, et al. Abiraterone acetate in patients with metastatic castration-resistant prostate cancer and prior therapy with ketoconazole: a Prostate Cancer Clinical Trials Consortium study. J Clin Oncol 2011; 29 (abstract 4500). 14. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17:3461-7. 15. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26:1148-59. 16. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003; 21: 1232-7. 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Soc 1958; 53:457-81. 18. Pond GR, Armstrong AJ, Galsky MD, Wood BA, Leopold L, Sonpavde G. Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: implications for prior therapy in clinical trials. Urol Oncol 2013; 31:1457-63.
Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment Rahul Aggarwal,1 Anna Harris,1 Carl Formaker,1 Eric J. Small,1 Arturo Molina,2 Thomas W. Griffin,3 Charles J. Ryan1 Abstract In this study, clinical outcomes after docetaxel therapy in 23 patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with abiraterone acetate (AA) were retrospectively evaluated. Subsequent docetaxel therapy led to ‡ 50% prostate-specific antigen (PSA) decline in 11 patients (48%) of patients; this outcome was not affected by pattern of AA resistance. The PSA response rates suggest that docetaxel and AA are not cross-resistant; however, further prospective study is required. Introduction/Background: Docetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies. Patients and Methods: Patients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed. Results: We identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to 30% PSA decline in 15 patients (65%) and 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy. Conclusion: In this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Androgen signaling, Cross-resistance, Chemotherapy, PSA response, Subsequent therapy
Introduction Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of the disease, and accounts for more than 29,000 deaths 1 Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 2 Janssen Research & Development, Menlo Park, CA 3 Janssen Research & Development, Los Angeles, CA
Submitted: Feb 6, 2014; Revised: Mar 10, 2014; Accepted: Mar 11, 2014 Address for correspondence: Rahul Aggarwal, MD, 1600 Divisadero St B745, San Francisco, CA 94143 Fax: 415-353-7093; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.03.010
annually in the United States.1 Within the past decade, multiple new therapeutic modalities have produced declines in serum prostatespecific antigen (PSA) and objective tumor responses, lengthened overall survival, and palliated symptoms in patients with mCRPC. Such therapies include taxane-based chemotherapy, radiopharmaceuticals, immunotherapy, androgen synthesis inhibitors such as abiraterone acetate (AA), and potent androgen receptor (AR) antagonists, including enzalutamide.2-8 In current clinical practice, patients are often treated sequentially with single-agent therapy until the time of disease progression or cumulative toxicity. Several key questions have emerged within the paradigm of sequential therapy for mCRPC: (1) Is there an optimal sequence of therapy?
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Outcomes With Docetaxel After Abiraterone in mCRPC (2) Does previous therapy with one therapeutic modality result in cross-resistance to other modalities? (3) Can subcategorizing patients on the basis of previous patterns of treatment resistance have predictive utility to help guide the choice of subsequent treatment? It is not known whether previous therapy with an androgen synthesis inhibitor results in cross-resistance to therapy with antitubule agents, such as docetaxel. If cross-resistance exists between these modalities of therapy, primary resistance to androgen synthesis inhibitors might be predictive of refractoriness to subsequent treatment with docetaxel. Some retrospective studies have suggested the potential for cross-resistance between androgen synthesis inhibitors, including ketoconazole and AA, and subsequent taxane-based chemotherapy,9 and others have failed to demonstrate compelling evidence for cross-resistance.10 In one retrospective study, AA-refractory patients were defined as those without PSA decline > 50% from baseline.9 In this subgroup of AA-refractory patients, no patients had a decline in PSA with subsequent docetaxel therapy.9 Taxane-mediated inhibition of AR nuclear transport and ARmediated gene transcription might provide the mechanistic link for potential cross-resistance with androgen signaling inhibition.11,12 It is hypothesized that previous therapy with potent inhibitors of the androgen signaling pathway, including AA, might lead to the emergence of treatment-resistant subclones of cancer cells that are less “androgen responsive” and thus less likely to respond to subsequent docetaxel chemotherapy. The objective of the current study was to evaluate potential crossresistance between androgen synthesis inhibitors and taxane-based chemotherapy. In this retrospective analysis of an independent cohort of patients with mCRPC who had disease progression with AA therapy, we examined disease outcomes with subsequent treatment with docetaxel. For this analysis, patients with radiographic stability for at least 8 months or PSA decline 50% from baseline were considered to have acquired resistance, and all others to have primary AA resistance. The cutoff for radiographic disease stability of at least 8 months was chosen because this was the observed approximate median radiographic progression-free survival in the prednisone with placebo control arm in the phase III study of AA in chemotherapy-naive mCRPC.5
Methods
The timing and choice of therapy after AA, and methods of response assessment, were per the discretion of the treating physician. Docetaxel schedules included weekly regimens (35 mg/m2 weekly; n ¼ 2) or every-3-week dosing (ranging from 60 to 75 mg/m2 every 3 weeks; n ¼ 21), all with concomitant prednisone. Patients who were concurrently treated with carboplatin or investigational therapies in addition to docetaxel were not included in this analysis. The duration of docetaxel therapy was per individual treating physician. Reasons for treatment discontinuation were assessed retrospectively. Each patient had signed an institutional review board (IRB)approved, protocol-specific informed consent form in accordance with federal and institutional guidelines before initiating treatment with AA. The subsequent retrospective review of outcomes after docetaxel therapy was IRB-approved.
Statistical Methods and Data Analysis Retrospective data collected included baseline patient characteristics at the start of docetaxel therapy such as validated prognostic factors in mCRPC, baseline PSA, Gleason score at the time of diagnosis, presence of visceral metastases, and use of opioid analgesics for cancer-associated pain.16 The maximal PSA percent decline from baseline was determined using all known serum PSA determinations obtained during therapy. Patients were categorized as experiencing PSA declines 30% and 50% from baseline if confirmed using repeat PSA measurement at least 4 weeks after the initial measurement, consistent with PCWG2 guidelines.15 The Kaplan-Meier product limit method was used to estimate the median overall survival from the date of first dose of docetaxel.17 Patients were censored at the date last known alive for the analysis of overall survival. Patients were subdivided into those with primary versus acquired AA resistance. Acquired AA resistance was defined as patients who experienced a PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression with AA. All other patients were defined as having primary AA resistance. Outcomes after docetaxel therapy according to subgroups of patients with primary or acquired resistance to AA were assessed using descriptive statistics. No formal statistical comparisons were performed between subgroups.
Study Population and AA Treatment Schedule
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Patients with mCRPC who were treated with AA until the time of disease progression in phase I/II (NCT00473746) and III (NCT00887198) clinical trials and had available data on outcomes with subsequent docetaxel chemotherapy were included in this retrospective, single-institution analysis. The eligibility criteria for the clinical trials of AA have been reported.5,13 Patients were chemotherapy-naive and had metastatic prostate cancer with disease progression despite castrate levels of serum testosterone (< 50 ng/dL). In the phase I study, the dose of AA ranged from 250 to 1000 mg/d, with or without concomitant prednisone. In the phase II and III studies, patients received standard dosing (AA 1000 mg/d in modified fasting state concomitantly with prednisone 5 mg orally twice daily). Patients were treated with AA until the time of disease progression according to Prostate Cancer Working Group (PCWG) or PCWG2 criteria,14,15 unacceptable toxicity, or study withdrawal.
Clinical Genitourinary Cancer Month 2014
Results Outcomes With Previous AA Therapy and Baseline Patient Characteristics Twenty-three patients who experienced disease progression while taking AA and were subsequently treated with docetaxel between 2007 and 2013 were included in this retrospective analysis, including 11 (48%) treated with AA in the phase III randomized study (subsequent unblinding of phase III treatment allocation allowed identification of patients with previous AA therapy). The distribution of AA dosing is shown in Table 1. Fifteen patients (65%) were treated at the standard dosing of AA (1000 mg/d in a modified fasting state with prednisone 5 mg twice daily). Outcomes for AA therapy are shown in Table 1. Twelve patients (52%) experienced a 50% decline from baseline in serum PSA with AA treatment. Fifteen patients (65%) discontinued AA because of radiographic or clinical progression and 8 (35%) because of PSA progression; the median
Rahul Aggarwal et al Table 1 Outcomes With Previous AA Therapy and Baseline Characteristics at the Start of Docetaxel Treatment Characteristic
Patient cohort (n [ 23)
Outcomes With Previous AA Therapy Dose and administration of previous AA therapy, n (%) 250 mg/d
1 (4)
500 mg/d
3 (13)
750 mg/d
2 (9)
1000 mg/d
17 (74)
With prednisone
15 (65)
Without prednisone
8 (35)
Maximal PSA decline 50% from baseline during previous AA therapy, n (%)
12 (52)
Median duration of previous AA therapy, months (range)
7.4 (2.2-43.0)
Reason for AA discontinuation, n (%) PSA PD Radiographic or clinical PD Median duration from AA discontinuation to docetaxel treatment initiation, months (range)
8 (35) 15 (65) 2.7 (0.2-14.7)
Intervening therapies between AA discontinuation and docetaxel treatment initiation, n (%) Any
8 (35)
Ketoconazole
6 (26)
Nilutamide
1 (4)
Diethylstilbestrol
1 (4)
Baseline Characteristics at the Start of Docetaxel Treatment Median age, years
67
Gleason grade at time of diagnosis, n (%) 6 7 8 Median baseline PSA, ng/mL (range)
2 (9) 4 (17) 17 (74) 260 (19-15,190)
Opioid analgesic use, n (%)
15 (65)
Visceral metastases, n (%)
2 (9)
Abbreviations: AA ¼ abiraterone acetate; PD ¼ progressive disease; PSA ¼ prostate-specific antigen.
duration of AA therapy was 7.4 months (range, 2.2-43.0 months). Eight patients (35%) received intervening therapies between AA treatment discontinuation and initiation of docetaxel, most of whom (n ¼ 6) received ketoconazole. Baseline patient characteristics at the start of subsequent docetaxel chemotherapy are shown in Table 1. The median duration between AA discontinuation and first dose of docetaxel chemotherapy was 2.7 months (range, 0.2-14.7 months). Most patients (n ¼ 15; 65%) required opioid analgesics for bone metastasisassociated pain at the start of docetaxel, and the median baseline serum PSA was 260 ng/mL (range, 19-15,190 ng/mL).
Outcomes With Docetaxel Therapy After Previous AA Therapy Clinical outcomes with docetaxel therapy after previous AA therapy are shown in Table 2. Fifteen patients (65%) experienced 30%
PSA decline from baseline, and 11 patients (48%) had 50% maximal PSA decline (Fig. 1). Seven patients (30%) discontinued docetaxel as a result of either adverse events or a break from chemotherapy in the absence of disease progression. The median duration of docetaxel therapy was 4.3 months (range, 2.1-9.8 months). The median overall survival from date of first dose of docetaxel was 12.4 months (95% confidence interval [CI], 8.219.6), with death events observed in 21 of 23 patients. From the start of AA treatment, the median overall survival was 27.2 months (95% CI, 23.6-35.3). The treatment interval between completion of AA and initiation of docetaxel did not appear to influence subsequent outcomes with docetaxel treatment. Dichotomizing the patient cohort into subgroups greater and less than the median interval of 2.7 months between AA discontinuation and docetaxel initiation, the 50% PSA response rate with docetaxel treatment and median overall survival from start of docetaxel were similar between the 2 subgroups (45% and 50%; 12.1 and 12.7 months, respectively).
Outcomes in Subgroups of Patients With Primary and Secondary Resistance to Previous AA Therapy Patients were subdivided into those with primary (n ¼ 9) or acquired (n ¼ 14) resistance to AA using definitions outlined in the Patients and Methods section. The baseline patient characteristics were similar in the 2 cohorts (data not shown). The clinical outcomes are shown in Table 2. The probability of 30% and 50% PSA decline from baseline during docetaxel therapy was numerically similar between subgroups, as was the median duration of docetaxel therapy. Likewise, despite a longer median overall survival from the start of AA in the subgroup of patients with acquired AA resistance (35.3 and 24.8 months, respectively, in acquired and primary AAresistant subgroups), the median overall survival from the start of subsequent docetaxel therapy was similar between the 2 subgroups (12.4 and 12.2 months, respectively) (Fig. 2). The dose level of AA did not appear to affect the patterns of AA resistance or subsequent outcomes with docetaxel treatment. Of the 15 patients who received standard AA dosing (1000 mg/d with prednisone), 6 (40%) had primary resistance to AA and the median overall survival from start of subsequent docetaxel treatment was 12.1 months. Of the 8 patients who received nonstandard AA dosing (< 1000 mg/d with or without concomitant prednisone), 3 (37.5%) had primary resistance to AA and the median duration of overall survival from start of docetaxel was 12.6 months. An alternate definition of primary versus acquired resistance was evaluated in which patients who did not experience any serum PSA decline with previous AA treatment were classified as having mCRPC with primary AA resistance (n ¼ 5); all others were classified as having acquired AA resistance (n ¼ 18). The use of alternate definitions of primary and acquired AA resistance yielded a similar pattern of results. Patients with primary AA resistance using this alternate definition had a shorter median survival from start of AA treatment compared with acquired AA-resistant patients (24.7 months and 34.3 months, respectively), but similar probabilities of PSA decline from baseline during docetaxel treatment (PSA decline 30% in 3 of 5 [60%] and 11 of 18 [61%] patients, respectively) and similar median overall survival from the start of docetaxel therapy (13.1 months and 11.9 months, respectively).
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Outcomes With Docetaxel After Abiraterone in mCRPC Table 2 Outcomes With Docetaxel Therapy According to Pattern of Previous Treatment Resistance to Abiraterone
Characteristic
Overall Patient Cohort (n [ 23)
Previous Primary AA Resistancea (n [ 9)
Previous Acquired AA Resistancea (n [ 14)
Starting Docetaxel Dose, n (%) 35 mg/m2 weekly
3 (13)
2 (22)
60 mg/m every 3 weeks
3 (13)
2 (22)
1 (7)
75 mg/m2 every 3 weeks
17 (74)
5 (56)
12 (86)
2
1 (7)
Maximal PSA Decline ‡ 30%, n (%)
15 (65)
6 (67)
9 (64)
Maximal PSA Decline ‡ 50%, n (%)
11 (48)
4 (44)
7 (50)
Reason for treatment discontinuation, n (%) PSA PD
9 (39)
6 (67)
3 (21)
Radiographic or clinical PD
5 (22)
2 (22)
3 (21)
Adverse event
3 (13)
1 (11)
2 (14)
Treatment break
4 (17)
0
4 (17)
Death
2 (9)
0
2 (14)
Median Duration of Docetaxel , months (range)
4.3 (2.1-9.8)
4.3 (2.1-9.5)
4.6 (2.6-9.8)
Follow-Up Treatments Received After Discontinuation of Docetaxel, n% Any
8 (35)
3 (33)
5 (36)
Cabazitaxel
3 (13)
1 (11)
2 (14)
Carboplatin
3 (13)
1 (11)
2 (14)
Enzalutamide
1 (4)
Radium-223
1 (4)
0
1 (7)
1 (11)
0
Median Overall Survival From First Dose of Docetaxel, Months (95% CI)
12.4 (8.2-19.6)
12.2 (6.6-19.6)
12.4 (7.0-22.5)
Median Overall Survival From First Dose of AA, Months (95% CI)
27.2 (23.6-35.3)
24.8 (11.1-30.6)
35.3 (21.7-38.4)
Abbreviations: AA ¼ abiraterone acetate; PD ¼ progressive disease; PSA ¼ prostate-specific antigen. a Acquired AA resistance was defined as patients who experienced a PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression using AA. All other patients were defined as having primary AA resistance.
Discussion
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The results of the current retrospective analysis suggest a lack of cross-resistance between previous AA treatment and subsequent docetaxel chemotherapy in patients with mCRPC. Nearly half of the patients experienced a 50% PSA decline from baseline during docetaxel treatment. There appeared to be no discernible association between outcomes with AA treatment and subsequent response to docetaxel. Patients with previous primary AA resistance had PSA response proportions and median overall survival from the start of docetaxel similar to patients with previous acquired resistance to AA. Although the definitions of primary and acquired AA resistance are arbitrarily defined in this analysis, PSA and radiographic criteria were used, consistent with PCWG2 guidelines.15 The observation that the median overall survival from start of AA therapy appeared to be shorter in patients with primary versus acquired resistance to AA adds validity to the definition of AA resistance used in this analysis. The use of an alternative definition of primary resistance to AA, defined as no PSA decline during AA therapy, also yielded similar outcomes with docetaxel for those with primary versus acquired AA resistance. The potential for cross-resistance between androgen synthesis inhibitors and docetaxel-based chemotherapy has been assessed preliminarily in several other retrospective studies. An analysis of the effect of the older-generation androgen synthesis inhibitor, ketoconazole, on subsequent outcomes in docetaxel-based chemotherapy
Clinical Genitourinary Cancer Month 2014
in a randomized phase III clinical trial found no differences in outcomes with respect to overall survival, progression-free survival, objective response rates, or PSA declines among those with and without previous ketoconazole exposure.18 That study had the
Figure 1 Maximal PSA Decline From Baseline During Subsequent Docetaxel Treatment According to Primary Versus Acquired Resistance to Previous Treatment With AA
Abbreviations: AA ¼ abiraterone acetate; PSA ¼ prostate-specific antigen.
Rahul Aggarwal et al Figure 2 Kaplan-Meier Curve of Overall Survival From (A) Date of First Docetaxel and (B) Start of Treatment AA for Patients With Primary or Acquired Resistance to AA
Abbreviation: AA ¼ abiraterone acetate.
limitation of using ketoconazole, a less potent and selective androgen synthesis inhibitor than AA, but did assess outcomes with subsequent docetaxel therapy within the framework of a large, cooperative-group, randomized, prospective study. In a separate single-institution retrospective analysis of 35 patients who received docetaxel after AA, only nine patients (26%) experienced 50% decline from baseline in PSA.9 Furthermore, in this analysis, patients with primary AA resistance, defined as those without a > 50% PSA decline from baseline, did not have a subsequent response to docetaxel, which led to the authors’ conclusion of evidence of cross-resistance because of a partial shared mechanism of action between androgen synthesis inhibitors and taxane-based chemotherapy.9 The baseline characteristics of patients in this study were comparable to those included in the current analysis with respect to age and sites of disease. In our study, the patient cohort was more likely to have pain requiring opioid analgesics, and a larger proportion had Gleason grade 8 disease at the time of diagnosis. In the current study, it is noteworthy that the median overall survival of 12.4 months from the start of docetaxel treatment was numerically shorter than the median survival of 18.9 months with every-3-week docetaxel treatment observed in the previous registrational phase III study (TAX327).7 Furthermore, the median duration of docetaxel therapy (4.3 months) was shorter than in the previous phase III study (7.1 months).7 This might potentially reflect true cross-resistance between previous AA and subsequent
docetaxel treatment with respect to overall survival. Alternatively, the observed duration of docetaxel treatment and overall survival might reflect a patient cohort with more adverse disease features at the start of chemotherapy, including a greater median baseline PSA, a greater median Gleason grade, and a greater proportion of patients requiring opioid analgesics compared with the phase III docetaxel trial population,7 and a shorter duration of AA treatment and median survival from start of AA treatment compared with the phase III trial of AA in chemotherapy-naive patients.5 Furthermore, the current study cohort received a greater number of previous systemic therapies for mCRPC compared with the TAX327 study cohort, and this might also influence prognosis in the absence of a specific effect on outcomes with docetaxel. Using a validated prognostic nomogram in mCRPC,16 the predicted median overall survival from the start of docetaxel was 6 months in the current study cohort, further reflecting a patient population with higher-risk disease compared with previous studies with docetaxel-based chemotherapy in mCRPC. Clear limitations of the current study include a small sample size and retrospective design, with possibility of selection bias; variability with respect to the lower dose of AA used in patients treated in the phase I study; and variability in the time interval between discontinuation of androgen synthesis inhibitors and initiation of subsequent therapy. Furthermore, the median duration of AA therapy in the current study cohort (7.4 months) was shorter than in the phase III studies of abiraterone,5 and 8 patients (35%) discontinued AA for PSA-only progression. These factors might influence the degree of “androgen responsiveness” and sensitivity to subsequent taxanebased chemotherapy. Ultimately, the current study results highlight the need for prospective studies to assess for an effect of previous therapy targeting the androgen signaling axis on subsequent outcomes with taxanebased chemotherapy for men with advanced prostate cancer.
Conclusion The results of the current study suggest that patients with acquired or primary resistance to previous treatment with AA have similar PSA response rates and overall survival with subsequent docetaxel treatment in mCRPC. The observed PSA response rates suggest that there is no cross-resistance between these modalities, but prospective data are required to validate definitions of primary versus acquired resistance to androgen-targeting agents in mCRPC and to address the potential for cross-resistance with taxane-based chemotherapy.
Clinical Practice Points Several new therapies for patients with mCRPC have improved
clinical outcomes, including reducing serum PSA, objective tumor responses, and improved overall survival. These therapies include taxane-based chemotherapy, androgen synthesis inhibitors, AR antagonists, immunotherapies, and radiopharmaceuticals. The optimal sequence of therapies for mCRPC is increasingly relevant and remains poorly understood. One retrospective study has reported cross-resistance between androgen synthesis inhibitors, ketoconazole, and AA, and subsequent taxane-based chemotherapy, and another study did not confirm this hypothesis. In this study we retrospectively evaluated this potential crossresistance between AA and subsequent docetaxel in an independent
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Outcomes With Docetaxel After Abiraterone in mCRPC cohort of 23 patients with mCRPC who had disease progression with AA therapy and were subsequently treated with docetaxel. Almost half of patients had a 50% PSA decline from baseline during docetaxel treatment; there was no discernible association between outcomes with AA and subsequent response to docetaxel. Patients with acquired AA resistance (PSA decline > 50% from baseline or radiographically stable disease for 8 months, with subsequent disease progression during AA treatment) versus primary AA resistance (all other patients) were also evaluated. Patients with primary AA resistance and acquired AA resistance had similar PSA response and median overall survival from the start of docetaxel treatment. These results suggest a lack of cross-resistance between these modalities, but further prospective evaluation is needed to understand cross-resistance with taxane-based chemotherapy and better define primary versus acquired resistance to androgentargeting agents in mCRPC.
Acknowledgments Writing assistance was provided by Hajira Koeller, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC.
Disclosure Arturo Molina and Thomas W. Griffin are employees of Janssen Research & Development and own stock in Johnson & Johnson. Charles J. Ryan has received honoraria from Janssen. The remaining authors have stated that they have no conflicts of interest.
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