Prostate Cancer: Drugs and Their Side Effects Victor Mcpherson MD, Msc, FRCSC Assistant Professor Division of Urology, Department of Surgery Mcgill University

05/05/2021

Prostate Cancer: Drugs and their side effects Victor McPherson MD, MSc, FRCSC Assistant Professor Division of Urology, Department of Surgery McGill University

COI Declaration

TYPE OF AFFILIATION NAME OF ORGANIZATION DETAILS / DATE (from/to)

TerSera May 26 2020 I am a member of an advisory board or similar committee for a Abbvie Oct 15 2020, Feb 25 2021 for-profit or non-profit organization

I have received payment from a for-profit or non-profit TerSera Travel funding to GU ASCO Conference organization (including gifts, etc...) 2020

I am currently participating in or have participated in a clinical Bristol-Myers Squibb BCG and immunotherapy in non muscle trial within the past two years invasive bladder cancer

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Learning Objectives – Anti Androgen Drugs and their side effects

-Overview of Prostate Cancer drugs: Focus on Anti-androgens -Non Steroidal Anti-Androgens -Bicalutimide -Androgen Deprivation Therapy -GnRH Antagonists -LHRH Agonists -Androgen Receptor Antagonists -Enzalutimide -Apalutimide -CYP17 Inhibitor -Abiraterone

Prostate Cancer Therapeutic Landscape

Adapted from: https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-prostate-cancer/119166-asco-gu-2020-treatment- selection-in-cspc-considerations-now-and-downstream-in-an-evolving-therapeutic-landscape-discussion-of-abstracts-82-and-162.html

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Non Steroidal Anti-Androgens

- Competitive antagonists of androgen receptor - NB: *Partial Agonists - Bicalutimide/Casodex most commonly used - ->50mg PO Daily - ->Used to suppress testosterone flare from LHRH agonists - ->Used in total androgen blockade (limited use currently) Cancer Care Ontario: https://www.cancercareontario.ca/en/drugformulary/drugs/bicalutamide

Non Steroidal Anti-Androgens

- Side effects: - Diarrhea (10%) -Fatigue - Gynecomastia and breast tenderness: more common in monotherapy (38%) - Hot flashes: monotherapy (12%) - Erectile function not significantly altered with bicalutamide monotherapy Cancer Care Ontario: https://www.cancercareontario.ca/en/drugformulary/drugs/bicalutamide BC Cancer Agency: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Bicalutamide_monograph_1October2011.pdf

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Non Steroidal Anti-Androgens

Cancer Care Ontario: https://www.cancercareontario.ca/en/drugformulary/drugs/bicalutamide

GnRH Antagonists and LHRH Agonist

https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/96381-assessment-of-cardiovascular-risk-with-the-use-of- androgen-deprivation-therapy-for-prostate-cancer-everyday-urology-full-text-article.html

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LHRH Agonists

- LHRH Agonist mechanism of action: - Overactivation of hypothalamus-pituitary axis leads to suppression - Temporary spike in Testosterone seen: NB in patients with high volume PCa - Can block with NSAA

- Eligard (Leuprolide Acetate); 1/3/4/6 month depo injections - Zoladex (Goserelin Acetate); 1/3 - Lupron (Leuprolide Acetate); 1/3/4/6 - Trelstar (Triptorelin); 1/3/6

GnRH Antagonists

- Direct GnRH Antagonist - Degarelix/Firmagon - 240mg SC loading dose - 80mg SC q monthly - Injection site reactions common - Possibly lower risk of cardiovascular toxicity – ongoing area of research

BC Cancer: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Degarelix_monograph_1Feb2015.pdf

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https://www.cua.org/system/files/Guidelines/7355_Guideline_ADT_Epub.pdf

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ADT Side Effects

• Retrospective data: • Cardiac Events HR 1.38 in retrospective study • Cardiovascular mortality HR 1.17 • Highest risk among men with pre-exisiting CVD  Controversy regarding LHRH gonists vs GnRH Antagonists

https://www.cua.org/system/files/Guidelines/7355_Guideline_ADT_Epub.pdf

ADT Side Effects

• Hot Flash Medications – NB None Health Canada Approved for this indication • Venlafaxine (Effexor) 75 mg orally daily • Medroxyprogesterone acetate (Provera) 20 mg orally daily • Cyproterone acetate (Androcur) 100 mg orally daily • Gabapentin (Neurontin) 900 mg orally daily • Megestrol acetate (Megace) 20 mg orally twice daily

https://www.cua.org/system/files/Guidelines/7355_Guideline_ADT_Epub.pdf

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ADT Side Effects

https://www.cua.org/system/files/Guidelines/7355_Guideline_ADT_Epub.pdf

Androgen Receptor Antagonists

Rajaram P, Rivera A, Muthima K, Olveda N, Muchalski H, Chen QH. Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer. Molecules. 2020 May 24;25(10):2448. doi: 10.3390/molecules25102448. PMID: 32456317; PMCID: PMC7287767.

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Enzalutimide

-Enzalutimide -First 2nd generation androgen receptor antagonists - 80-160mg PO Daily

BC Cancer: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Degarelix_monograph_1Feb2015.pdf

Enzalutimide

-Enzalutimide - Most common: Fatigue, MSK pain, ↑lfts, diarrhea, androgen deprivation symptoms, edema, headache, HTN, dizziness, insomnia - Increased seizure risk

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Enzalutamide_monograph_1Oct2015.pdf

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Enzalutimide

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Enzalutamide_monograph_1Oct2015.pdf

Enzalutimide

https://www.cancercareontario.ca/sites/ccocancercare/files/enzalutamide.pdf

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Apalutimide

- Apalutimide/Erleada -2nd generation androgen receptor antagonist - 120-240mg PO Daily

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Apalutamide_monograph.pdf

Apalutimide

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Apalutamide_monograph.pdf

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Apalutimide

- Rash: up to 25%; some grade 3-4 - median onset within 3 months - usually resolves within 2 months - recurs in up to 50% with rechallenge - treatment: corticosteroids and antihistamines +/- dose reduction/interruption/discontinuation

- Siezure: increased risk with apalutimide as well

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Apalutamide_monograph.pdf

Apalutimide

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Apalutamide_monograph.pdf

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Apalutimide

https://www.cancercareontario.ca/en/drugformulary/drugs/apalutamide

Abiraterone

Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer Neeraj Agarwal, Thomas E Hutson, Nicholas J Vogelzang, and Guru Sonpavde Future Oncology 2010 6:5, 665-679

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Abiraterone

- Abiraterone/Zytiga - CYP17 Inhibitor - 1000mg PO Daily + 5,g PO daily prednisone

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Abiraterone_monograph.pdf

Abiraterone

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Abiraterone_monograph.pdf

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Abiraterone

-Fatigue

- Mineralocorticoid effects: ACTH increase - hypertension/hypokalemia/fluid retention - concomitant use of prednisone prevents

- Hepatotoxicity; usually w/in 3 months

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Abiraterone_monograph.pdf

Abiraterone

http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Abiraterone_monograph.pdf

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Abiraterone

https://www.cancercareontario.ca/en/drugformulary/drugs/abiraterone

References

1. https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-prostate-cancer/119166-asco-gu-2020-treatment- selection-in-cspc-considerations-now-and-downstream-in-an-evolving-therapeutic-landscape-discussion-of-abstracts-82-and- 162.html 2. Cancer Care Ontario: https://www.cancercareontario.ca/en/drugformulary/drugs/bicalutamide 3. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Bicalutamide_monograph_1October2011.pdf 4. https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/96381-assessment-of-cardiovascular-risk-with- the-use-of-androgen-deprivation-therapy-for-prostate-cancer-everyday-urology-full-text-article.html 5. BC Cancer: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Degarelix_monograph_1Feb2015.pdf 6. https://www.cua.org/system/files/Guidelines/7355_Guideline_ADT_Epub.pdf 7. Rajaram P, Rivera A, Muthima K, Olveda N, Muchalski H, Chen QH. Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer. Molecules. 2020 May 24;25(10):2448. doi: 10.3390/molecules25102448. PMID: 32456317; PMCID: PMC7287767. 8. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Enzalutamide_monograph_1Oct2015.pdf 9. https://www.cancercareontario.ca/sites/ccocancercare/files/enzalutamide.pdf 9. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Apalutamide_monograph.pdf 10. https://www.cancercareontario.ca/en/drugformulary/drugs/apalutamide 11. Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer Neeraj Agarwal, Thomas E Hutson, Nicholas J Vogelzang, and Guru Sonpavde Future Oncology 2010 6:5, 665-679 12. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Abiraterone_monograph.pdf 13. https://www.cancercareontario.ca/en/drugformulary/drugs/abiraterone

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