Abiraterone & Subsequent EnzalutamideTherapy in Metastatic Castration-Resistant

Prostate Cancer: A Retrospective Study

Shabnam Rehman, PGY3SUNY at Buffalo-Catholic Health SystemRoberto Pili, MD Roswell Park Cancer Institute

Background

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

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

Definition

Castrate-resistant prostate cancer (CRPC) is defined as 2consecutive rises in prostate-specific antigen (PSA) levelsobtained at intervals of greater than 2 weeks and/ordocumented disease progression based on findings fromcomputed tomography scan and/or bone scan, bone pain orobstructive voiding symptoms with castrate levels oftestosterone (≤50ng/dl)

• Mechanisms of castration resistance:

- AR amplification/overexpression

- gain-of-function AR mutations (mostly in the ligand-binding domain)

- intracrine androgen production

- overexpression of AR cofactors (sensitizing cells to low levels of androgens)

- ligand independent AR activation by cytokines or growth factors

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

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Evolution of androgen receptor targeted therapy for advanced prostate cancer.

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

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

Tran C, et al. Science 2009;324:787–90. & Hu R, et al. Expert Rev Endocrinol Metab 2010;5:753–64

Prostate-target cell

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 studyshowed increased overall survival with Enzalutamide compared to placeboin men with CRPC (18.6 months vs. 13.6 months)

deBonoJS,Logothetis CJ,MolinaA,etal.Abiraterone andincreasedsurvivalinmetastaticprostatecancer.TheNewEnglandjournalofmedicine.2011;364(21):1995‐2005RyanCJ,SmithMR,deBonoJS,etal.Abiraterone inmetastaticprostatecancerwithoutpreviouschemotherapy.TheNewEnglandjournalofmedicine.2013;368(2):138‐148

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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 Abirateronetreatment 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 (additionaltreatment/s after Abiraterone, before Enzalutamide)

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

• The PSA response along with clinical and/or radiological parameters used to assess the diseaseprogression.

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

Variable AE ATE P ValueMedian 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 at the start of Aberaterone

30.23 (0.42-292.96) 38.79 (3.1-578.46) 0.28

Median AbirateroneTreatment

4.25 months(1.15-20.7) 3.22 (0.62-13.34) 0.67

Median Enzalutamide Treatment

3.27 months(0.79-9.36) 2.66(0.99-5.52) 0.079

Median time interval 0.11 months 6.6months 0.001

Results

(AE: Abiraterone Enzalutamide ; ATE: Abiraterone Chemotherapy Enzalutamide)

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

Patients with adverse effects on Enzalutamide

11 (79%) 7 (78%) 1.000

Reason for stopping Enzalutamide

Toxicity 0 1 (11%)

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

Death 2 (14%) 3 (33%)

Ongoing Enzalutamide treatment1 (7%) 1 (11%) 1.000

Treatment specific outcomes

(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).

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

Median progression time (months)

3-month progression Median progression time (months)

3-month progression

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

1a. Abiraterone 1b. Enzalutamide

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

Enzalutamide (Fig. 1c)Median

progression time (months)

3-month progression

AE 2.8 74.4%

ATE 1.4 58.3%

1c. Enzalutamide

Figure 3. Kaplan Meier analysis showing 50% PSA progression on Enzalutamide (1c)

Abiraterone (Fig. 2a) Enzalutamide (Fig 2b)

Median progression time (months)

3-month progression Median progression time (months)

3-month progression

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)

2a 2b

Median OS (months)

3-year survival

AE Not reached

70.1%

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,IleanaE,etal.Antitumour activityofabiraterone acetateagainstmetastaticcastration‐resistantprostatecancerprogressingafterdocetaxel andenzalutamide (MDV3100).Annalsofoncology:ESMO.2013;24(7):1807‐1812

NoonanKL,NorthS,Bitting RL,ArmstrongAJ,Ellard SL,ChiKN.Clinicalactivityofabiraterone acetateinpatientswithmetastaticcastration‐resistantprostatecancerprogressingafterenzalutamide.Annalsofoncology:ESMO.2013;24(7):1802‐1807

Bianchini D,Lorente D,Rodriguez‐VidaA,etal.Antitumour activityofenzalutamide (MDV3100)inpatientswithmetastaticcastration‐resistantprostatecancer(CRPC)pre‐treatedwithdocetaxel andabiraterone.Europeanjournalofcancer(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-drug interaction. Feedback mechanisms observed by either agent are dissipated. Clinical trial 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

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Acknowledgements

Dr. Henri T Woodman

Dr. Roberto Pili

Dr. Athar Battoo

Dr. Christopher Attwood

Dr. Danchaivijitr Pongwuth

Thank You