mCRPC: Sequencing Androgen Receptor-Targeted Therapies, Chemotherapy, and Radium

Educational Objectives

The goal of this program is to improve management of prostate cancer with androgen receptor targeted therapies. After hearing and assimilating this program, the clinician will be better able to:

1. Identify patients harboring mutations known to respond to therapy with poly adenosine diphosphate-ribose polymerase inhibitors.
2. Use bipolar androgen therapy to resensitize patients with castration-resistant prostate cancer to antiandrogen medications.

Summary

Introduction: underutilization of newer medications for cancer in the United States are a consequence of affordability; patient-related factors (eg, performance status, age, comorbidities) influence the approach to disease; the clinician must consider duration of prior therapies and patient response

Burden of disease: castration resistant prostate cancer may be oligometastatic or oligoprogressive; metastasis location (eg, bone, liver, pelvic lymph nodes) affects outcomes; patients with nodal metastasis do well; patients with bony metastasis have an intermediate prognosis; prognosis with liver metastasis is poor; doubling time of prostate specific antigen (PSA) is a surrogate for decision making with respect to progression

Phenotypes and biomarkers: phenotypes include neuroendocrine and anaplastic cancers; BRCA and other biomarkers are important; image-based biomarkers (eg, PSMA) are relevant; relevant clinical trial options may be available; adverse event profiles and patient preferences are important

“Sequence matters” approach: adopted by the National Comprehensive Cancer Network; abiraterone acetate, enzalutamide, or docetaxel are the preferred regimens for patients who underwent conventional androgen deprivation therapy (ADT); patients who had prior docetaxel are given hormone therapy (abiraterone acetate or enzalutamide) or cabazitaxel; carboplatin is used for neuroendocrine cancers; use of mitoxantrone is less common; minimal data is available on use of radium plus sipuleucel-T; docetaxel is the current preferred regimen for patients who have had prior therapy with novel hormones (eg, abiraterone, enzalutamide, apalutamide, darolutamide); additional treatment options may be molecularly driven (eg, olaparib, rucaparib); radium is used for symptomatic bony metastases; sipuleucel-T may be used in patients who are mostly asymptomatic

Biomarkers: molecular and image-based biomarkers are used to guide therapy; olaparib is approved for use in mutated homologous recombination repair genes (BRCA1, BRCA2, PALB2, RAD51D) following novel hormone therapy which may include docetaxel; rucaparib is indicated for post abiraterone, enzalutamide, or docetaxel for BRCA1 and BRCA2 only; pembrolizumab is approved for any cancer with mismatch repair genes (MSH2, MSH6); prostate specific membrane antigen positron emission tomography (PSMA PET) is an image-based biomarker

Molecular biomarkers: tissue-based or circulating DNA-based; metastatic castration-resistant prostate cancer (mCRPC) is heterogeneous; DNA repair defects are present in ≈25% of patients; a survival benefit has been seen with the use of polyadenosine diphosphate–ribose polymerase (PARP) inhibitor with olaparib vs standard hormonal agents in patients with mCRPC; PARP inhibitors work best for defects in BRAC1, BRAC2, and PALB2; the effect on rare genes (eg, ATM, CDK12, CHEK2) are not definitive; circulating tumor DNA (ctDNA) is useful to detect defects in BRCA1, BRCA2, and ATM; the significance of abnormalities in the CHIP gene is unknown; pembrolizumab is approved and produces robust responses in patients with high mutational loads and mismatch repair gene alterations

Theranostics and combination therapy: precision medicine works in ≈20% of patients; theranostics involves placing a radionuclide on a linker and a ligand to target cell surface proteins for identification (PSMA PET) or treatment (Lutetium-177-PSMA-617 [Pluvicto]); demonstration of prolongation of survival and improvements in radiographic progression-free survival led to Food and Drug Administration approval of Lutetium-177-PSMA-617; a combination of PARP inhibitor with novel hormone therapy is beneficial for BRCA mutations, as outlined by the PROpel trial (Saad et al, 2023)

ctDNA: useful for treatment selection and as a biomarker for disease response and progression; pembrolizumab is useful for rare BRAF mutations

Oligopolyprogression: patients may initially respond to systemic therapy and later show recurrence; radiation therapy is useful in cases of oligoprogression; Lendorf et al (2021) compared docetaxel given every 2 wk compared with docetaxel given every 3 wk; improvement in overall survival was seen with dosing every 2 wk; the 2 wk regimen was better tolerated with fewer cases of neutropenia and less fatigue compared with the 3 wk regimen; abiraterone is currently prescribed at 1000 mg/day without food; abiraterone is effective at a dose of 250 mg/day if given with food; outcomes for both regimens were similar

High-dose testosterone: used for select patients; may cause acceleration of the disease in some patients; high-dose testosterone should be reserved for patients in whom progression is not expected to be harmful; Denmeade et al (2021) compared use of bipolar androgen therapy (BAT) vs enzalutamide for the management of CRPS; PSA response rates were similar in both groups; some patients had an acceleration in PSA; the PSA response rate for enzalutamide after crossover was 78%, which suggests re-sensitization after BAT therapy; patients who respond after BAT therapy may have a long duration of response

Readings

Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer. J Clin Oncol. 2021;39(12):1371-1382. doi:10.1200/JCO.20.02759; Labriola MK, Atiq S, Hirshman N, et al. Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies. Prostate Cancer Prostatic Dis. 2021;24(2):301-309. doi:10.1038/s41391-020-00299-9; Lendorf ME, Petersen PM, Svendsen AS, et al. Effectiveness of docetaxel for metastatic hormone-sensitive prostate cancer in clinical practice. Eur Urol Open Sci. 2021;24:25-33. Published 2021 Jan 6. doi:10.1016/j.euros.2020.12.006; Lubberman FJE, Benoist GE, Gerritsen W, et al. A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics. Cancer Chemother Pharmacol. 2019;84(6):1179-1185. doi:10.1007/s00280-019-03952-w; Markowski MC, Kachhap S, De Marzo AM, et al. Molecular and clinical characterization of patients with metastatic castration resistant prostate cancer achieving deep responses to bipolar androgen therapy. Clin Genitourin Cancer. 2022;20(2):97-101. doi:10.1016/j.clgc.2021.08.001; Morote J, Aguilar A, Planas J, et al. Definition of castrate resistant prostate cancer: New insights. Biomedicines. 2022;10(3):689. Published 2022 Mar 17. doi:10.3390/biomedicines10030689; Pianou NK, Stavrou PZ, Vlontzou E, et al. More advantages in detecting bone and soft tissue metastases from prostate cancer using 18F-PSMA PET/CT. Hell J Nucl Med. 2019;22(1):6-9. doi:10.1967/s002449910952; Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108. doi:10.1016/S1470-2045(23)00382-0; Shirotake S, Umezawa Y, Okabe T, et al. A case of castration-resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy. Transl Androl Urol. 2020;9(2):819-823. doi:10.21037/tau.2020.01.20.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Sartor has been a consultant at Advanced Accelerator Applications (AAA), Astellas Pharma Inc., AstraZeneca, Bayer, Blue EarthDiagnostics Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Merck, Moyvant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics. He has received grant support from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio. Members of the planning committee reported nothing relevant to disclose. Dr. Sartor's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Sartor was recorded at Southwest Prostate Cancer Symposium, held April 13-15, 2023, in Scottsdale, AZ, and presented by Grand Rounds in Urology. For information about upcoming CME activities from this presenter, please visit grandroundsinurology.com. Audio Digest thanks the speakers and Grand Rounds in Urology for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

UR462303

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.