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Abiraterone & Subsequent Enzalutamide Therapy in Metastatic -Resistant Cancer: A Retrospective Study

Shabnam Rehman, PGY3 SUNY at Buffalo-Catholic Health System Roberto Pili, MD Roswell Park Cancer Institute Background

• Deprivation Therapy (ADT) or castration, either medical or surgical, is the gold standard treatment for metastatic

• After 1-3 years these tumors become resistant to ADT- Castration Resistant Prostate Cancer (CRPC) Definition

Castrate-resistant prostate cancer (CRPC) is defined as 2 consecutive rises in prostate-specific antigen (PSA) levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from computed tomography scan and/or bone scan, bone pain or obstructive voiding symptoms with castrate levels of (≤50ng/dl) • Mechanisms of castration resistance: - AR amplification/overexpression - gain-of-function AR mutations (mostly in the -binding domain) - intracrine androgen production - overexpression of AR cofactors (sensitizing cells to low levels of ) - ligand independent AR activation by cytokines or growth factors

• Development of novel agents like Abiraterone and Enzalutamide targeting AR signaling at different stages

Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration‐resistant tumor growth. Cancer research. 2008;68(11):4447‐4454. Nat Rev Clin Oncol. 2014 Jun;11(6):365-76. doi: 10.1038/nrclinonc.2014.72. Epub 2014 May 20.

Evolution of targeted therapy for advanced prostate cancer.

Wong YN1, Ferraldeschi R2, Attard G3, de Bono J2

Prostate-target cell

AR=androgen receptor. DHEA=. DHT=. T=testosterone.

Tran C, et al. Science 2009;324:787–90. & Hu R, et al. Expert Rev Endocrinol Metab 2010;5:753–64 Abiraterone • Level 1 evidence for use in both pre- and post-docetaxel settings

Enzalutamide • Approved by FDA in August 2012 for the treatment of castration resistant metastatic prostate cancer patients post docetaxel therapy (AFFIRM study showed increased overall survival with Enzalutamide compared to placebo in men with CRPC (18.6 months vs. 13.6 months)

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine. 2011;364(21):1995‐2005 Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. The New England journal of medicine. 2013;368(2):138‐148

Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration‐resistant prostate cancer: a phase 1‐2 study. Lancet. 2010;375(9724):1437‐1446. Practice pattern

• From 4/28/11 – 12/10/12

Docetaxel based Chemo Abiraterone Enzalutamide

• From 12/10/12 – 4/25/14

Abiraterone Chemotherapy Enzalutamide Study Rationale

Greater time interval, with additional intervening treatments, between the Abiraterone treatment and subsequent Enzalutamide may confer more clinical benefit.

Endpoints

• Primary

Difference in PSA response in 2 groups: AE (Abiraterone followed by Enzalutamide ) & ATE (Abiraterone followed by chemotherapy and then Enzalutamide)

• Secondary

1. Difference in clinical benefit measured objectively by progression free and overall survival 2. Time to PSA progression by 30 and 50 percent Methodology

• Database: cancer registry and institutional network database ( Jan 2005-Dec 2013)

• Eligibility : - mCRPC patients who had received treatment at RPCI with both Abiraterone and Enzalutamide

- At least PSA 2 measurements after Abiraterone and Enzalutamide treatments

• Retrospective chart review

• Patients categorized into 2 groups : AE (Abiraterone followed by Enzalutamide) and ATE (additional treatment/s after Abiraterone, before Enzalutamide)

• Intervening treatment/s: GnRH , chemotherapeutic agents and Sipuleucel-T.

• The PSA response along with clinical and/or radiological parameters used to assess the disease progression. Statistical analysis

• Descriptive statistics and comparisons between the two groups were done

• Overall survival, disease progression and PSA response on treatment evaluated

• All analysis was conducted in SAS v9.3 (Cary, NC) at a significance level of 0.05 Results

Variable AE ATE P Value Median Age 63.5 yrs (51-73) 62.5 yrs (57-77) 0.52 Histology Adenocarcinoma Gleason score >7 10/14 5/9 Median Baseline PSA 30.23 (0.42-292.96) 38.79 (3.1-578.46) 0.28 at the start of Aberaterone Median Abiraterone 4.25 months(1.15-20.7) 3.22 (0.62-13.34) 0.67 Treatment

Median Enzalutamide 3.27 months(0.79-9.36) 2.66(0.99-5.52) 0.079 Treatment

Median time interval 0.11 months 6.6months 0.001

(AE: Abiraterone Enzalutamide ; ATE: Abiraterone Chemotherapy Enzalutamide) Treatment specific outcomes

Outcomes AE (n=14) ATE (n=9) P-value

Patients with adverse effects on 11 (79%) 7 (78%) 1.000 Enzalutamide

Reason for stopping Enzalutamide

Toxicity 0 1 (11%)

Progression 11 (79%) 4 (45%) 0.177

Death 2 (14%) 3 (33%)

Ongoing Enzalutamide treatment 1 (7%) 1 (11%) 1.000

(AE: Abiraterone followed by Enzalutamide; ATE: Abiraterone followed by chemotherapy & then Enzalutamide) • During Enzalutamide treatment, 14.3% patients in AE (without intervening

treatment) compared to 11.1% in ATE (with intervening treatment) group

achieved 30% reduction in serum PSA levels (p=1.000)

• The median time to achieve a maximum PSA decline on Enzalutamide, was

2.35 and 2.8 months for AE and ATE respectively (p=1.000). 1a. Abiraterone 1b. Enzalutamide

Abiraterone (Fig. 1a) Enzalutamide (Fig. 1b)

Median progression time 3-month progression Median progression time 3-month progression (months) (months)

AE 4.1 43.7% 1.7 81.8% ATE 10.9 44.4% 1.0 87.5%

Figure 3. Kaplan Meier analysis showing 30% PSA progression on Abiraterone (1a) and Enzalutamide (1b). 1c. Enzalutamide

Enzalutamide (Fig. 1c) Median 3-month progression time progression (months) AE 2.8 74.4%

ATE 1.4 58.3%

Figure 3. Kaplan Meier analysis showing 50% PSA progression on Enzalutamide (1c) 2a 2b Abiraterone (Fig. 2a) Enzalutamide (Fig 2b) Median progression 3-month progression Median progression 3-month progression time (months) time (months)

AE 4.4 30.8% 3.3 35.7%

ATE 3.5 37.5% 2.8 74.6%

Figure 2. Kaplan Meier Analysis showing the disease progression on Abiraterone (2a) and Enzalutamide (2b) Median OS 3-year (months) survival Not AE 70.1% reached ATE 54.8 66.7%

Figure 1: The Kaplan-Meier analysis showing the overall survival (OS) in AE and ATE cohorts. • A significant association between the Abiraterone treatment length and progression on

Enzalutamide: longer Abiraterone treatment associated with higher likelihood of

progression on Enzalutamide (p=0.008). Conclusion

• Longer time interval and/or intervening cancer treatment between Abiraterone and

subsequent Enzalutamide therapy did not favorably alter the disease progression in

mCRPC

• Prolonged Abiraterone treatment, irrespective of the intervening time interval, was

significantly associated with a higher likelihood of progression on later Enzalutamide

therapy Now what to do?

• Challenge to the physician : the best sequence and timing of each drug in mCRPC patients

• Very few retrospective studies show modest activity for both Abiraterone followed by Enzalutamide or vice-versa with > 30% PSA response 11-40%

Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of against metastatic castration‐resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Annals of oncology: ESMO. 2013;24(7):1807‐1812

Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration‐resistant prostate cancer progressing after enzalutamide. Annals of oncology : ESMO. 2013;24(7):1802‐1807

Bianchini D, Lorente D, Rodriguez‐Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration‐resistant prostate cancer (CRPC) pre‐treated with docetaxel and abiraterone. European journal of cancer (Oxford, England : 1990). 2014;50(1):78‐84. Future directions

• Elucidation of resistance mechanisms

• Rationale for combined treatment for synergy Conclusions: ENZA+ AA combination has a favorable safety profile, without clinically meaningful PK drug- . Feedback mechanisms observed by either agent are dissipated. information: NCT01650194 Limitations

• Sample size

• Information bias: medical records might not clearly reflect the reasoning behind the

individual patients receiving the specific intervening cancer treatment/s

• Recall bias: certain patient specific socioeconomic and cultural factors might influence

the decision making process which might not be evident on review of medical records References Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, et al. Androgen receptor status in localized and locally progressive refractory human prostate cancer. Am J Pathol 1994;144:735-46.

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Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 2009;69:4434-42.

Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15.

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Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 2008;15:841-9. Acknowledgements

Dr. Henri T Woodman

Dr. Roberto Pili

Dr. Athar Battoo

Dr. Christopher Attwood

Dr. Danchaivijitr Pongwuth Thank You