Evolving Treatment Paradigm for Patients With Advanced Prostate Cancer: The Emerging Role of Androgen Receptor Pathway Inhibitors

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1 Evolving Treatment Paradigm for Patients With Advanced Prostate Cancer: The Emerging Role of Androgen Receptor Pathway Inhibitors The Treatment Plan for Patients With Advanced Prostate Cancer: Where Do Androgen Receptor Pathway Inhibitors Belong? Karim Fizazi, MD, PhD Gustave Roussy Cancer Institute Villejuif, France An Evidentiary Review of Emerging Androgen Receptor Pathway Inhibitors Matthew Smith, MD, PhD Harvard Medical School Massachusetts General Hospital Boston, Massachusetts, USA Go online to complete the post-test and earn your CME credit!

2 CME Details Funding Disclosure This activity is supported by an educational grant from Bayer HealthCare Pharmaceuticals. Activity Description and Educational Objectives In this activity, experts in the management of prostate cancer discuss sequencing strategies with current and emerging androgen receptor pathway inhibitors (ARPIs) in order to maximise patients survival and quality of life. Upon completion of this activity, participants should be better able to: Identify patient- and disease-related factors that may affect treatment decisions and response to therapy with androgen receptor pathway inhibitors (ARPIs) Describe how current treatment plans may change for patients with advanced prostate cancer, given the recent and emerging clinical trial data Explain the similarities and differences between current and emerging ARPIs Target Audience This activity has been designed to meet the educational needs of medical oncologists, urologists, and other clinicians involved in prostate cancer management. Faculty Disclosure Statement / Conflict of Interest Policy Oakstone Publishing, LLC has assessed conflict of interest with its faculty, authors, editors, and any individuals who were in a position to control the content of this CME activity. Any identified relevant conflicts of interest were resolved for fair balance and scientific objectivity of studies utilized in this activity. Oakstone Publishing s planners, medical reviewers, and editorial staff disclose no relevant financial relationships with commercial interests. Course Director Karim Fizazi, MD, PhD Head of Department, Department of Cancer Medicine Gustave Roussy Cancer Institute Villejuif, France Karim Fizazi, MD, PhD, has a financial interest/relationship or affiliation in the form of: Honoraria from Astellas Pharma EMEA; Janssen-Cilag Pharmaceuticals SA; and Sanofi. Advisory Board for Astellas Pharma EMEA; Bayer AG; Clovis Oncology, Inc.; ESSA Pharma, Inc.; Genentech, Inc; Janssen-Cilag Pharmaceuticals SA; Orion Corporation; and Sanofi. Faculty Matthew Smith, MD, PhD Professor of Medicine Harvard Medical School Director, Genitourinary Malignancies Program Massachusetts General Hospital Boston, Massachusetts, USA Matthew Smith, MD, PhD, has a financial interest/relationship or affiliation in the form of: Consultant for Amgen Inc; Bayer AG; ESSA Pharma Inc.; Janssen-Cilag Pharmaceuticals SA; and Pfizer Inc. Advisory Board for Amgen Inc; Bayer AG; ESSA Pharma Inc.; Janssen-Cilag Pharmaceuticals SA; and Pfizer Inc. PeerVoice Medical Director Serena Welch has no financial interests/relationships or affiliations in relation to this activity. Disclosure of Unlabelled Use The faculty of this educational activity may include discussions of products or devices that are not currently labelled for use in certain jurisdictions. 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3 Karim Fizazi, MD, PhD Gustave Roussy Cancer Institute Villejuif, France The Treatment Plan for Patients With Advanced Prostate Cancer: Where Do Androgen Receptor Pathway Inhibitors Belong? Conceptual Framework for the Management of Advanced Prostate Cancer (St Gallen APCCC) Efficacy Associated With Approved ARPIs Abiraterone and Enzalutamide for mcrpc (Post-Docetaxel) COU-AA-31: Abiraterone/Pred a,1 AFFIRM: Enzalutamide b,2 Castration-aïve PC ADT M M CRPC Management of patients with non-metastatic (M) CRPC OS, % HR,.74 (95% CI, ) P <.1 + Pred ABI + Pred OS, % HR,.63 (95% CI, ) P <.1 EZA M1 ADT M1 1st Line M1 2nd Line M1 3rd Line Time, mo Data are from multiple trials and cannot be directly compared Time, mo a COU-AA-31 study design: Phase 3 double-blind trial wherein patients ( = 1,195) were randomised to receive either abiraterone acetate + prednisone (n = 797) or placebo + prednisone (n = 398). 1 b AFFIRM study design: Phase 3 double-blind trial wherein patients ( = 1,199) were randomised to receive either enzalutamide (n = 8) or placebo (n = 399). 2 Abbreviation(s): ADT: androgen-deprivation therapy; APCCC: Advanced Prostate Cancer Consensus Conference; CRPC: castration-resistant prostate cancer (PC); M: no evidence of metastases on imaging; M1: metastases documented on imaging. Reference(s): Gillessen S et al. Ann Oncol. 215;26: Karim Fizazi, MD, PhD: Hello, this is Karim Fizazi from Institut Gustave Roussy in Villejuif, France. Welcome to this educational activity on treatment of advanced prostate cancer. We're going to review what is the current role of androgen receptor pathway inhibitors in the treatment sequence; and also, we'll look at how this role may evolve in the near future. So, this slide is derived from the St Gallen Consensus Meeting in 215, and it's really showing you the framework for advanced prostate cancer. So some patients have nonmetastatic disease, but we already know that they have advanced disease because the disease has become resistant to castration, which is M CRPC; while some other patients are entering the disease upfront with evidence of metastasis what we call M1 castration-naïve prostate cancer. Abbreviation(s): ABI: abiraterone acetate; ARPI: androgen receptor pathway inhibitor; EZA: enzalutamide; mcrpc: metastatic CRPC; OS: overall survival; : placebo; Pred: prednisone. Reference(s): 1. Fizazi K et al; COU-AA-31 Investigators. Lancet Oncol. 212;13: Scher HI et al; AFFIRM Investigators. Engl J Med. 212;367: Abiraterone and enzalutamide are the two approved androgen receptor pathway inhibitors that showed efficacy in large phase 3 trials. This is, for example, the COU-31 and AFFIRM randomised phase 3 trials, respectively, showing that approximately a 3% reduction in the risk of death can be achieved when using these agents in the post-docetaxel setting. Whatever the pathway, the disease evolves to metastatic castration-resistant disease (mcrpc), and we are talking about first-line, second-line, third-line, etc, CRPC treatments. 3

4 Safety Associated With Approved ARPIs Abiraterone and Enzalutamide for mcrpc Summary of Safety Profile for Abiraterone 1 Most Common AEs Peripheral oedema Hypokalaemia Hypertension Urinary tract infection Other Important AEs Cardiac disorders Hepatotoxicity Fractures Allergic alveolitis Summary of Safety Profile for Enzalutamide 2 Most Common AEs Fatigue Hot flush Headache Hypertension Other Important AEs Falls Fractures Cognitive disorders eutropenia Seizure a a Seizure occurred in.5% of patients treated with enzalutamide;.1% of patients treated with placebo; and.3% of patients treated with bicalutamide. Cross-Resistance Between Approved ARPIs Abiraterone and Enzalutamide Enzalutamide Abiraterone Author Duration of Second Therapy â PSA 5% Median PFS Loriot et al mo 3% 2.7 mo oonan et al wk 3% 3.8 mo Abiraterone Enzalutamide Author Duration of Second Therapy â PSA 5% Median PFS Schrader et al mo 29% - Badrising et al mo 21% - Bianchini et al mo 23% - Schmid et al mo 1% - Brasso et al mo 18% - Abbreviation(s): AE: adverse event. Reference(s): 1. Abiraterone acetate Summary of Product Characteristics (SmPC). en_gb/document_library/epar_-_product_information/ human/2321/wc pdf. Accesed April 6, Enzalutade SmPC. en_gb/document_library/epar_-_product_information/ human/2639/wc pdf. Accessed April 6, 217. Let's briefly review what is the safety pattern of these agents. Hypertension and a slight excess of cardiac disorders were seen in patients treated with abiraterone. ow, fatigue and cognitive impairment emerge as side effects that are linked to enzalutamide use. This might be related to the fact that enzalutamide penetrates the blood-brain barrier. This agent is associated with a risk of seizure, and this is, of course, something, again, to pay attention to. We need to question the patient about seizures. Finally, again, we need to pay attention to hypertension and generally speaking, cardiac events. When considering treating your patients with these agents, you really need to ask the patient whether he has a previous history of cardiac disorders and perhaps you need to refer him to the cardiologist before starting treatment. Also, because these treatments are generally well tolerated, they are now used [as approved] more and more in patients who are chemotherapy-naïve. Abbreviation(s): PFS: progression-free survival; PSA: prostate-specific antigen. Reference(s): Zhang T et al. Expert Opin Pharmacother. 215;16: Unfortunately, cross-resistance between the two agents is quite high. If you're using enzalutamide after abiraterone, perhaps a slightly higher proportion of patients will benefit, but generally speaking, this is probably not the best sequence to consider, at least for most patients. Efficacy Associated With Chemotherapy Post-Abiraterone for mcrpc Abiraterone Docetaxel a,1 4% of patients with â PSA 5% a Median TTP a of 7.6 mo a COU-AA-31 post-hoc analysis: Assessment of clinical responses to DOC as first subsequent therapy among patients ( = 1) who progressed following protocol-specified treatment with abiraterone. Median duration of DOC was 4.2 months. 1 b Study design: Antitumour activity of cabazitaxel assessed in patients with mcrpc and progressive disease after treatment with DOC and abiraterone ( = 79). Median duration of cabazitaxel was 6 cycles. 2 Docetaxel Abiraterone Cabazitaxel b,2 35% of patients with â PSA 5% b Median TTP b of 4.4 mo Abbreviation(s): DOC: docetaxel; TTP: time to progression. Reference(s): 1. de Bono JS et al. Eur Urol. 217;71: Al akouzi et al. Eur Urol. 215;68: On the other hand, most patients receiving docetaxel when they have failed abiraterone seem to benefit. So, even if there is perhaps some cross-resistance between the two drugs, it's probably not as high as the cross-resistance between abiraterone and enzalutamide. This is also true when treating patients with cabazitaxel when they have failed abiraterone and actually in this experience, they had also failed docetaxel. So obviously, if the patient is fit enough to get chemotherapy, most patients will actually derive some benefit. 4

5 The Evolving Role of ARPI Therapy for Advanced Prostate Cancer Evolving role of ARPIs for advanced prostate cancer LATITUDE is a large phase 3 trial looking at really nasty metastatic prostate cancer, and nasty because they have to have at least two poor-risk factors, out of visceral metastasis, at least 3 bone metastases, and a Gleason score of 8 or greater. Metastatic CSPC LATITUDE STAMPEDE ARASES M CRPC ARAMIS SPARTA PROSPER Combination with alternative mcrpc treatments CT CT A second trial is also looking at this question for more allcomers patients with prostate cancer about to start ADT and we see in an academic trial called STAMPEDE. So the two trials are really expected very, very soon. Abbreviation(s): CSPC: castration-sensitive prostate cancer. ow let's talk about where the use of these ARPI agents is heading. One obviously is to use them upfront, so earlier in the course of the disease. For example, in patients with castrationsensitive or castration-naïve metastatic disease so patients who are just entering this disease with evidence of metastasis. A second potential indication in the near future might be nonmetastatic CRPC [M CRPC] so patients with nondetectable lesions that are progressing while on castration therapy. Finally, the third strategy might be to combine these drugs, either together, or with other agents. Metastatic CSPC: Phase 3 Studies With Abiraterone Experimental Arm ABI + ADT + Pred ABI + ADT Control Arm ADT ADT Clinical Trial Identifier (Study ame) CT (LATITUDE) 1 Clinical State mcspc with 2 of the following: Visceral mets 3 Bone mets Gleason score 8 Prior Chemotherapy o CT (STAMPEDE) 2 mcspc o Abbreviation(s): mets: metastases; mcspc: metastatic CSPC. Reference(s): 1. ClinicalTrials.gov Identifier: CT Accessed March 3, ClinicalTrials.gov Identifier: CT clinicaltrials.gov/ct2/show/ct Accessed March 3, 217. Metastatic CSPC: Clinical Studies Assessing Docetaxel Treatment Survival Effect of Docetaxel in Patients With Early Metastatic Disease Control CHAARTED 136/393 GETUG-15 A/193 STAMPEDE (SOC ± DOC) 35/724 STAMPEDE (SOC + ZA ± DOC) 17/366 Treatment 11/397 A/ / /365 Overall.77 ( ) Heterogeneity χ 2 = 4.8; df = 3; P =.187; I 2 = 37.5% Favours SOC + DOC Favours SOC HR (95% CI).61 (.47-.8).9 ( ).76 ( ).85 ( ) Study design: Meta-analysis of three studies (CHAARTED, GETUG-15, STAMPEDE; = 2,992). For each trial, HRs of the effects of DOC or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) were extracted. Figure shown was for M1 disease. Abbreviation(s): A: not available; SOC: standard of care; ZA: zoledronic acid. Reference(s): Vale CL et al; STOpCaP Steering Group. Lancet Oncol. 216;17: In the meantime, after these trials were designed and conducted, docetaxel emerged as a standard of care for fit patients [good performance status] with castration-sensitive disease at least those patients with multiple bony metastasis or visceral disease. This is, for example, the meta-analysis of large phase 3 trials. The overall analysis resulted in a 23% reduction in the risk of death when docetaxel is, indeed, used upfront in these gentlemen. So this is for most of us, I guess, now a current standard. For patients with newly diagnosed metastatic prostate cancer, who are just about to start castration therapy, we are waiting for data from two trials testing the role of abiraterone on top of castration therapy. 5

6 Metastatic CSPC: St Gallen APCCC Expert Use of Docetaxel Q: Do you recommend ADT + docetaxel in patients with castration-naïve high-volume disease? For example, many experts see a role for early use of docetaxel in patients with: Multiple bony metastases Visceral metastases Majority, 5% o, 11% Minority, 39% Findings from the second St Gallen APCCC Expert Panel will be published soon We do have trials looking at whether next-generation ARtargeted drugs may make a difference. The ARASES phase 3 trial is really looking at whether ODM-21 (darolutamide) will further improve overall survival in a context of the patients who's treated with ADT plus docetaxel. So this will be a really complementary to the previous trials I just mentioned. ODM- 21 (darolutamide) is chemically different [from other ARPIs]; it doesn't penetrate the brain-blood barrier, which might be important because, part of the toxicity of enzalutamide, at least in some patients, might be related to the fact that it penetrates the brain and binds to the GABA receptor. Reference(s): Gillessen S et al. Ann Oncol. 215;26: M CRPC: Phase 3 Studies of Approved and Emerging ARPIs There is debate as whether this is true for all-comers, or whether we should restrict docetaxel use for patients with very advanced disease namely those with multiple bony metastases or those with visceral metastases. The experts just had the second St Gallen consensus meeting; most of us are now using docetaxel early in advanced prostate cancer. Experimental Arm Control Arm Enzalutamide Experimental Arm Control Arm (AR-59) Approved ARPI Clinical Trial Identifier (Study ame) CT23924 (PROSPER) 1 Clinical State High-risk a M CRPC Emerging ARPI b Clinical Trial Identifier Clinical State (Study ame) CT (SPARTA) 2 High-risk a M CRPC Prior Chemotherapy o Prior Chemotherapy o (ODM-21) CT22614 (ARAMIS) 3 High-risk a M CRPC o Metastatic CSPC: Phase 3 ARASES Study Assessing (ODM-21) Phase 3 randomised, double-blind, multinational study Patients ( ~1,3) with: Histologically or cytologically confirmed disease Metastatic, hormone-sensitive disease Candidates for ADT/DOC ECOG PS /1 Adequate bone marrow, liver, and renal function 1 R 1 + ADT + DOC + ADT + DOC Planned completion date: August 222 Primary endpoint OS Key secondary endpoints Time to CRPC Time to subsequent therapy SSE-FS Time to: First SSE Opioid use Pain progression Worsening physical symptoms a High risk defined as PSA doubling time 1 months. b Agent currently unapproved for CRPC. Reference(s): 1. ClinicalTrials.gov Identifier: CT CT Accessed April 4, ClinicalTrials.gov Identifier: CT clinicaltrials.gov/ct2/show/ct Accessed April 4, ClinicalTrials.gov Identifier: CT clinicaltrials.gov/ct2/show/ CT Accessed April 4, 217. Abbreviation(s): ECOG PS: Eastern Cooperative Oncology Group performance status; OS: overall survival; SSE: symptomatic skeletal events; SSE-FS: SSE-free survival. Reference(s): ClinicalTrials.gov Identifier: CT Accessed March 3, 217. The next question will be, should we use androgen receptor pathway inhibitors on top not only of castration therapy, but also on top of docetaxel? ow, a very different clinical situation, again, is that of patients with non-mcrpc [M CRPC]. So again, we do have the ARAMIS phase 3 trial testing ODM-21 (darolutamide), also the SPARTA phase 3 trial looking at AR-59 (apalutamide), and the PROSPER phase 3 trial looking at enzalutamide. With AR-59 (apalutamide), honestly, we don't necessarily see much different as compared with enzalutamide. In the phase 1/2 development, you also don't see much difference. 6

7 Metastatic CRPC: Phase 3 Combination Strategies With Approved and Emerging ARPIs Experimental Arm a + ABI/Pred Enzalutamide + ABI/Pred Control Arm a Emerging agent, currently unapproved for CRPC. Clinical Trial Identifier Clinical State Abiraterone + CT mcrpc o Enzalutamide CT mcrpc o Prior Chemotherapy So, as a conclusion, I would say that really the evolution of treatment for patients with advanced prostate cancer has really evolved tremendously in the last five years or so. We are mostly using androgen receptor pathway inhibitors quite early in the course of mcrpc, in patients who are usually naïve of chemotherapy. The role of androgen receptor pathway inhibitors in two very important situations namely, M1 castration-sensitive prostate cancer and non metastatic M CRPC will be clarified very soon because we're expecting several major phase 3 trials to readout probably this year or next year. Reference(s): 1. ClinicalTrials.gov Identifier: CT CT Accessed April 4, ClinicalTrials.gov Identifier: CT clinicaltrials.gov/ct2/show/ CT Accessed April 6, 217. ow, another strategy, obviously, when you have a drug that is active is to try to combine it with another drug that is also active with perhaps a different mechanism of action. So there is a rationale to combine, for example, abiraterone together with enzalutamide. This is now being tested randomly versus enzalutamide. We're now using many agents sequentially; the ideal sequence is something that we don't really know for sure. ow having said that, the cross-resistance between these agents enzalutamide and abiraterone, for example is quite high. So, before using them sequentially, you really need to think twice whether it's the best thing to do for your patients instead of using another agent such as chemotherapy. Thank you very much for your kind attention. A very similar trial is also testing abiraterone plus placebo versus abiraterone plus AR-59 (apalutamide). This trial is currently enrolling patients. So hopefully we'll have data in one or two years from now. Summary: ARPI Therapy for Advanced Prostate Cancer Typically, used earlier in the disease course Is there a role for earlier use of ARPIs? What is the role of emerging novel ARPIs? Optimal sequencing of these agents is not well understood Metastatic CSPC? M CRPC? 7

8 Matthew Smith, MD, PhD Harvard Medical School Massachusetts General Hospital Boston, Massachusetts, USA An Evidentiary Review of Emerging Androgen Receptor Pathway Inhibitors Currently Approved Therapies for mcrpc: Moving From Palliation to Survival Benefit Evolving the Standard of Care for Advanced Prostate Cancer: Optimising ARPI Therapy Current ARPIs: Abiraterone and Enzalutamide Strontium-89 (RP) Mitoxantrone (CT) Samarium-153 (RP) Zoledronic Acid (BP) Docetaxel (CT) Denosumab (BP) Sipuleucel-T (IO) Abiraterone (ARPI) Cabazitaxel (CT) Enzalutamide (ARPI) FDA Approval Timeline Radium-223 (RP) Survival Palliation Emerging agents Proven efficacy for mcrpc management Can agents targeting the AR pathway be effective EARLIER in the apc treatment paradigm? Acceptable safety/ tolerability profile Can known safety and tolerability issues be minimised? ew ARPI options needed Abbreviation(s): ARPI: androgen receptor (AR) pathway inhibitor; BP: bisphosphonate; CT: chemotherapy; IO: immunotherapy; mcrpc: metastatic castration-resistant prostate cancer; RP: radiopharmaceutical. Reference(s): Adapted by: Matthew Smith, MD, PhD; March 217. Matthew Smith, MD, PhD: Hello, I m Dr. Matthew Smith, Professor of Medicine at Harvard Medical School, and Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center. Currently, there are six FDAapproved therapies for metastatic castration-resistant prostate cancer (mcrpc). These approved agents include two androgen receptor pathway inhibitors, abiraterone acetate and enzalutamide. Abiraterone acetate and enzalutamide are important parts of our toolbox for the management of advanced disease. Both drugs are approved for the treatment of mcrpc before and after docetaxel chemotherapy, based on Level 1 evidence for improved progression-free (PFS) and overall survival (OS). Abbreviation(s): apc: advanced prostate cancer. While abiraterone acetate and enzalutamide are well tolerated, there are some patients who, in fact, have unacceptable side effects with one or both of those agents, so there is an unmet need for drugs that are better tolerated. There s also a need to look at this class of agents in other clinical settings, including some settings where tolerability will be particularly important. For example, in the setting of non metastatic CRPC, there would be an expected long period of treatment, and in order for that to be acceptable, we would prefer to have agents that have an extremely favourable safety profile. Evolving the Standard of Care for Advanced Prostate Cancer: Can ARPIs Be Used Earlier in Disease Management? PSA COCETRATIO o detectable disease; asymptomatic Low-volume bone disease; asymptomatic High-volume bone disease; pain, fatigue, anaemia Visceral disease on-metastatic Metastatic and asymptomatic Metastatic and symptomatic TIME Opportunity for ARPIs earlier in apc paradigm? Use of current ARPIs abiraterone and enzalutamide Abbreviation(s): PSA: prostate-specific antigen. Reference(s): Lorente D et al. Lancet Oncol. 215;16:e279-e292. 8

9 This activity will review the role of novel androgen receptor pathway inhibitors in phase 3 clinical development, and how the ongoing clinical trials may shape the future use of this class of drugs in other important settings in prostate cancer, including non metastatic CRPC (non mcrpc) and hormonesensitive (or castration-sensitive) prostate cancer. In a phase 2 clinical trial, apalutamide demonstrated activity in mcrpc. Among 25 patients who were abiraterone acetate naïve, PSA response rate at 12 weeks was 88%. Among patients who had progression despite prior abiraterone acetate, response rates dropped to 22%, consistent with overlapping cross-resistance between the androgen pathway inhibitors. ovel ARPIs in Phase 3 Clinical Development: Approved ARPIs Abiraterone Enzalutamide (AR-59) Anti-androgen Structurally similar to enzalutamide High affinity for AR Crosses the BBB F 3 C C Emerging ARPIs O S F H O F 3 C C O S F Enzalutamide Abbreviation(s): BBB: blood-brain barrier. Reference(s): Toren PJ, Gleave ME. Transl Androl Urol. 213;2: Bambury RM, Rathkopf DE. Urol Oncol. 216;34: There are two novel androgen pathway inhibitors in phase 3 clinical development, apalutamide and darolutamide., formerly known as AR-59, is an antiandrogen that is structurally very similar to enzalutamide. Like enzalutamide, it also has a high affinity for the androgen receptor and crosses the blood-brain barrier. H O Metastatic CRPC: Phase 2 Safety Outcomes With All-Grade TEAE in >15% of Patients, % Fatigue ausea 48 Abdominal Pain Diarrhoea Dyspnoea Rash Arthralgia Abiraterone/Pred-aïve (n = 25) Post-Abiraterone/Pred (n = 21) Back Pain Cough Anaemia Hot Flush Decreased Appetite Dizziness Insomnia Abbreviation(s): TEAE: treatment-emergent adverse event (AE). Reference(s): Rathkopf DE et al; Clin Cancer Res. 217 Feb 17. pii: clincanres [Epub ahead of print]. doi:1.1158/ ccr The most common adverse events associated with apalutamide were fatigue, nausea, abdominal pain, and diarrhoea. otably, most of the adverse events were grade 1 or 2. Phase 3 Studies of Metastatic CRPC: Phase 2 Study With Disease Course 12-Wk PSA Change From Baseline in Abiraterone/Pred-aïve Patients, % Abiraterone/Pred-aïve (n = 25) PSA Response Rate, 88% 12-Wk PSA Change From Baseline in Post-Abiraterone/Pred Patients, % Post-Abiraterone/Pred-aïve (n = 21) PSA Response Rate, 22% High-risk localised/ LA apc CT (ATLAS) + GnRH + RT vs GnRH + RT + High-risk M CRPC CT (SPARTA) vs Low-volume mcspc CT (TITA) + ADT vs ADT + mcrpc CT ABI/Pred + apalutamide vs /Pred Study design: To evaluate the efficacy of apalutamide before or after treatment with abiraterone + prednisone in progressive mcrpc, abiraterone/prednisone-naïve (n = 25) and post-abiraterone/prednisone (n = 21) patients who had received 6 months of abiraterone/prednisone with progressive mcrpc without prior CT received apalutamide 24 mg/day. Abbreviation(s): Pred: prednisone. Reference(s): Rathkopf DE et al; Clin Cancer Res. 217 Feb 17. pii: clincanres [Epub ahead of print]. doi:1.1158/ ccr Abbreviation(s): ABI: abiraterone; ADT: androgen deprivation therapy; GnRH: gonadotropin-releasing hormone; LA: locally advanced; mcspc: metastatic castration-resistant prostate cancer; : placebo; RT: radiation therapy. Reference(s): Anantharaman A, Friedlander TW. Urol Oncol. 216;34:

10 There are currently four phase 3 clinical trials of apalutamide. The ATLAS study will evaluate the addition of apalutamide to androgen deprivation therapy (ADT) and radiation therapy for men with high-risk localised prostate cancer. The SPARTA study will evaluate apalutamide in men with high-risk non mcrpc. The TITA study will evaluate apalutamide in men with low-volume metastatic hormone-sensitive prostate cancer. Another study will evaluate the addition of apalutamide to abiraterone in men with mcrpc. Limited penetration of the blood-brain barrier also distinguishes darolutamide from other anti-androgens. In this non-clinical model, for example, the blood-brain-barrier penetration for darolutamide was only 3% compared with 19% and 29% for enzalutamide and apalutamide, respectively. The predicted lower blood-brain penetration and lower brain exposure with darolutamide may confer a safety advantage for darolutamide relative to other anti-androgens. This will be assessed in multiple ongoing large clinical trials. ovel ARPIs in Phase 3 Clinical Development: Metastatic CRPC: Phase 2 Study With (ARADES) Approved ARPIs Abiraterone Enzalutamide (ODM-21) Anti-androgen Structurally distinct from any known anti-androgens Great affinity for AR Emerging ARPIs CI C O (S) H H OH PSA Change From Baseline to Wk 12, % Chemotherapy- and CPY17i-aïve Patient Group PSA 5%: 5% (2 mg) 69% (4 mg) 86% (1,4 mg) 2 mg PSA Change From Baseline to Wk 12, % Post-CPY17i Patient Group PSA 5%: (2 mg) 1 18% (4 mg) 7% (1,4 mg) mg 1,4 mg Study design: To evaluate the safety, pharmacokinetics, and activity of darolutamide, the phase 1 portion of the open-label dose-finding study. In phase 2, patients were randomly assigned centrally, and stratified by previous CT and treatment with CPY17 inhibitors, to receive one of three daily doses of darolutamide (2 mg, 4 mg, and 1,4 mg). The primary endpoint in phase 2 was the proportion of patients with a PSA response ( 5% decrease in serum PSA) at week 12. Reference(s): Wong Y et al. at Rev Clin Oncol. 214;11: Moilanen A-M et al. Sci Rep. 215;5:127. Bambury RM, Rathkopf DE. Urol Oncol. 216;34: , formerly known as ODM-21, is also a potent anti-androgen; it is structurally distinct from other known anti-androgens. It also has a greater affinity for the androgen receptor. Comparative Penetration of the Blood-Brain Barrier by ARPIs Abbreviation(s): CPY17i: CPY17 inhibitor. Reference(s): Fizazi K et al. Lancet Oncol. 214;15: The efficacy of darolutamide in mcrpc has been demonstrated in a phase 2 clinical trial. Among patients with mcrpc and no prior exposure to abiraterone acetate or chemotherapy, PSA response rate was 86% at the highest dose studied. As expected, the PSA response rate was lower [7% among highest dose studied] among patients who had disease progression despite prior treatment with abiraterone acetate. Enzalutamide 19% BBB Penetration 1 3% Metastatic CRPC: Phase 2 Safety Outcomes With (ARADES) 6 29% Enzalutamide Brain/Plasma Ratio in Mouse, % a,2 a The very low access of darolutamide into the brain was confirmed with a quantitative whole-body autoradiography (QWBA) Abbreviation(s): QWBA: quantitative whole-body autoradiography. Reference(s): 1. Moilanen AM et al. European Cancer Congress 213 (ECC 213). Poster. globalassets/documents/rd/congress-posters/esmo-213- nonclinical-poster.pdf. Accessed April 13, Moilanen AM et al. Sci Rep. 215;5:127. Total AEs in 1% of Patients, % ausea Fatigue Bone Pain Abdominal Pain Back Pain Diarrhoea Haematuria Study design: Patients ( = 3) in this open-label phase 1 trial received a single 6-mg dose of darolutamide in capsules with food and one 6-mg dose of darolutamide tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 6 mg twice daily darolutamide taken with food in capsules. Reference(s): Massard C et al. Eur Urol. 216;69:

11 The most commonly reported adverse events associated with darolutamide were nausea, fatigue, bone pain, and abdominal pain. otably though, the rate of these adverse events was very low, between 3% and 13%, and the majority of adverse events were grade 1. While we always have to be careful about comparing between different phase 2 clinical trials these were not head-to-head trials the reported safety profile of darolutamide looked particularly favourable. Phase 3 Studies of Disease Course M CRPC CT22614 (ARAMIS) vs mcspc CT (ARASES) + ADT + DOC vs + ADT+ DOC There s limited evidence to suggest there would be marked differences in efficacy between the different androgen receptor pathway inhibitors. From a distance, it would appear that darolutamide is particularly well tolerated and that might confer advantages, particularly in the settings where there is an anticipated long period of exposure. We will look to the results of the ongoing studies to determine whether in fact that s the case. The results of ongoing phase 3 clinical studies will not only assess the value of these novel anti-androgens, but also evaluate the role of this class of agents in an earlier disease state, so if successful and approved and used in that setting, the drugs might be moved in front of abiraterone or enzalutamide. So, the landscape has already been transformed in recent years and will be transformed again in coming years, as the results of these clinical trials mature and we better understand the optimal way to use these agents. arrator: Thank you for participating in this PeerCME educational activity. To obtain your CME certificate, complete the required post-test and evaluation form. Abbreviation(s): DOC: docetaxel. Reference(s): Anantharaman A, Friedlander TW. Urol Oncol. 216;34: There are two ongoing phase 3 clinical trials of darolutamide in prostate cancer. The ARAMIS trial will evaluate darolutamide in men with high-risk non mcrpc. The ARASES trial evaluates ADT plus docetaxel, with or without darolutamide, in men with hormone-sensitive metastatic disease. Summary: Targeting the Androgen Receptor for Advanced Prostate Cancer Approved ARPIs Abiraterone Enzalutamide Emerging ARPIs Approved in both the pre- and post-docetaxel settings Comparable efficacy, evaluated in both ARPI-naïve and ARPI-experienced patients has lower BBB penetration a Role of these agents is evolving in various apc settings a In preclinical models. In summary, the androgen receptor is a validated target in prostate cancer. There are two novel anti-androgens in phase 3 clinical development., or AR-59, is structurally similar to enzalutamide, and is undergoing evaluation in four phase 3 clinical trials. is structurally distinct and is currently in phase 3 clinical development in two clinical trials. 11

12 Check out our curriculum website for more information and resources: CRPCTreatmentPlan.peercme.com Evolving Treatment Paradigm for [Theme] Patients With Advanced Prostate Cancer: The Emerging Role of Androgen Receptor Pathway Inhibitors This activity is supported by an educational grant from Bayer Healthcare Pharmaceuticals. About This PeerCME Activity PeerVoice and Oakstone Publishing, LLC, are responsible for the selection of this activity's topics, the preparation of educational content, and the distribution of this activity. The preparation of PeerCME activities is supported by written agreements that clearly stipulate and enforce the independence of PeerVoice, Oakstone Publishing, LLC, and the faculty presenters. The faculty may discuss unapproved products or uses of these products in certain jurisdictions. Faculty presenters have been advised to disclose any reference to an unlabelled or unapproved use. o endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our activities. o responsibility is taken for errors or omissions. For approved prescribing information, please consult the manufacturer's product monograph. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerVoice or any of its supporters , PeerVoice PeerVoice 114 Avenue of the Americas, 15th Floor ew York, Y 136