Learning Objectives

At the conclusion of the activity, participants will be able to:

• Identify the active agents and their mechanism of action in the management of nonmetastatic castration resistant prostate cancer (CRPC) and metastatic CRPC.
• Describe sequencing and indications for active treatment with approved agents in the management of nonmetatstic CRPC.
• Analyze the evidence and outcomes on the treatment of MO and M1 CRPC as outlined in the newly updated AUA CRPC guidelines.
• Improve diagnostic and therapeutic decision-making processes by illustrating the application of these guidelines in urological practice.
• Analyze breakthrough treatments in the management of advanced and metastatic hormone naïve prostate cancer.

Improvements in the understanding of genetic alterations and their impact on men with advanced prostate cancer (APC), advances in precision medicine and refinements in diagnostic imaging were some of the highlights of this year’s course. Consequently, the evaluation and treatment of men with advanced, metastatic, and castration resistant prostate cancer (CRPC) continues to evolve. This is important when considered in the context of a disease that results in the second leading cause of cancer deaths in men.¹ Improved overall survival (OS) with a multitude of different therapeutic agents and combinations, coupled with the success of earlier use of some already approved agents, have resulted in updates to these guidelines.

On one end of the spectrum within this disease state, treatment of men with metastatic CRPC (mCRPC) continues to evolve. In the past, once androgen deprivation therapy (ADT) failed, treatment of mCRPC was only palliative. However, landmark studies by Tannock² and Petrylak³ et al demonstrated that docetaxel improved OS in patients with mCRPC compared to mitoxantrone. Since then, the field has evolved with an explosion of new therapies. Recently, a multitude of additional therapeutics (abiraterone, sipuleucel-T, cabazitaxel, enzalutamide and radium-223) have demonstrated survival benefit and been approved by the U.S. Food and Drug Administration (FDA) based on clinical trials in men with mCRPC.^4-9 Now, some of these agents and others discussed are showing benefit earlier in the disease state, including the metastatic hormone sensitive (mHSPC) and nonmetastatic (M0 CRPC) setting.

At the virtual AUA 2021 meeting, we presented the updated APC Guidelines. One reason for the continued updates is the rapid evolution of the field. While new agents are undergoing clinical trials, other agents are moving up in the sequencing. We included 3 trials in patients with M0 CRPC using androgen targeted therapy. These trials resulted in a significant delay in metastasis-free survival (MFS). The first published study was the SPARTAN trial, a randomized trial comparing apalutamide vs placebo in M0 CRPC at high risk for metastasis.¹⁰ The investigators reported a highly significant improvement in MFS with use of apalutamide vs placebo in men at high risk for metastasis as determined by a prostate specific antigen doubling time of 10 months or less. This has resulted in the FDA approval of apalutamide for use in men with M0 CRPC. Using a similar trial design, results from PROSPER also demonstrated similar improvement in MFS in men with high risk M0 CRPC with use of enzalutamide.¹¹ A third study, ARAMIS, also demonstrated significant improvement in MFS in men with M0 CRPC using darolutamide as compared to placebo in high risk men with M0 CRPC.¹² In addition, the prolonged MFS and longer followup of these trials has resulted in positive OS outcomes.¹³ This now provides further evidence for the early use of these novel second generation antiandrogen agents in patients with M0 CRPC in order to not only delay metastases but also to prolong OS. Finally, the impact of next generation positron emission tomography (PET) scan imaging will continue to better identify patients with small volume metastases and should result in reclassification of patients in this disease state.

The course included review of the management of men with biochemical recurrence after failed local therapy. The importance of risk stratification was discussed, including clinical factors such as time to biochemical failure and prostate specific antigen doubling time, tumor grade and stage, all of which may impact initiation of treatment. For the truly high-risk patients with biochemical recurrence after failed local therapy, initiation of ADT may be appropriate and, when applied, consideration to intermittent therapy was discussed.¹⁴ Also discussed was the FDA approval of novel prostate-specific membrane antigen (PSMA) PET scans in the evaluation of high-risk patients for both staging and in the assessment of recurrent prostate cancer.^15,16 Both Gallium 68 PSMA-11 PET and ¹⁸F-DCFPyL, or PYLARIFY^®, are now FDA approved and will be changing the way we stage and ultimately treat men with APC. The course also emphasized the importance of germline testing in men with newly diagnosed APC.

The incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%.¹⁷ Also discussed was the role of genetic counseling in these prior to the germline testing.

Among men with mHSPC, we highlighted guidance on the management of mHSPC. We reviewed the trials demonstrating OS benefit with the addition of docetaxel chemotherapy to ADT from both the CHAARTED and STAMPEDE trials.^18,19 In the CHAARTED trial, the benefit was most pronounced among men with “high volume” metastatic disease as predefined in the study. In addition to studies demonstrating the benefit of docetaxel chemotherapy, the addition of androgen targeted therapy to traditional luteinizing hormone-releasing hormone therapy resulted in significant improvement in OS when compared to luteinizing hormone-releasing hormone therapy alone. Both abiraterone acetate plus prednisone and enzalutamide or apalutamide when combined with conventional ADT demonstrated significant OS benefit in men with mHSPC. Collectively, these studies demonstrate that men with mHSPC should be offered ADT plus one of these novel androgen-axis therapies or docetaxel chemotherapy.

Management of patients with mCRPC was also reviewed. Enzalutamide before chemotherapy in men with asymptomatic or mildly symptomatic mCRPC was discussed.⁹ The study demonstrated significant improvement in both OS and radiographic progression-free survival in patients treated with enzalutamide vs placebo. Previously, abiraterone plus prednisone was approved in the pre-chemotherapy setting as well.⁴ In addition, the use of an alpha emitting radionuclide therapy was discussed relative to the FDA approved use of radium-223 dichloride in men with mCRPC who are symptomatic from bone metastases and without visceral metastatic disease.⁸

In patients with mCRPC who are asymptomatic or have minimal symptoms with metastases and have received no prior docetaxel, clinicians should offer abiraterone plus prednisone, enzalutamide, docetaxel or sipuleucel-T. In this instance, sipuleucel-T is appropriate and will not be recommended for more severe symptoms, making it an important consideration in this early asymptomatic or minimally symptomatic setting.

Patients with symptomatic mCRPC, a good performance status and who have not previously received docetaxel are candidates for several approved agents. Clinicians should offer abiraterone plus prednisone, enzalutamide or docetaxel chemotherapy. For patients with symptomatic bone metastases and no visceral metastases, clinicians should offer radium-223. Amongst those with symptomatic mCRPC and prior docetaxel therapy with a good performance status, treatment with abiraterone + prednisone, cabazitaxel or enzalutamide should be offered. If the patient received abiraterone + prednisone or enzalutamide before docetaxel chemotherapy, they should be offered cabazitaxel. Patients with mCRPC with prior docetaxel treatment who are symptomatic with bone metastases and no visceral metastases should be offered radium-223.

One new area in this year’s course is the development of precision-based therapy with a new class of agents, poly (ADP-ribose) polymerase (PARP) inhibitors. The recent discovery that some men with APC carry or develop alterations in DNA-damage repair proteins has uncovered a new therapeutic area. In May 2020, the FDA approved 2 oral PARP inhibitors, rucaparib (TRITON2) and olaparib (PROfound), for the treatment of mCRPC.^20,21 The TRITON2 study assessed objective response to rucaparib as compared to additional hormonal therapy for mCRPC patients with germline or somatic BRCA1 or BRCA2 mutations who had disease progression despite previously receiving at least 1 novel hormone therapy and 1 chemotherapy. The PROfound study was positive, showing a significant prolongation of radiographic progression-free survival but also OS in the patients with mCRPC after at least 1 novel androgen directed therapy (and up to 1 chemotherapy) who had BRCA1, BRCA2, and ATM mutations treated with olaparib as compared to an additional hormonal agent. Both agents, and others in study, will be trialed in combination and in earlier phases of the APC disease state.

Among mCRPC patients who have progressed through therapy and have poor performance status, these patients should be offered supportive care. The goal of palliation is to prevent and relieve suffering, and to support the best possible quality of life for the patient and family. Palliative radiotherapy can be an option to control bone pain in some patients and should be offered. Alternatively, in select cases clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. Currently, due to the poor performance status, clinicians should not offer systemic chemotherapy or immunotherapy to these patients.

The guidelines also address bone health and indicate that all patients with CRPC should be offered preventive treatment (supplemental calcium, vitamin D) to reduce the risk of fractures and skeletal related events.²² Denosumab or zoledronic acid may be selected as preventive treatment for skeletal related events in patients with mCRPC and bone metastases.^23,24 The treatment of APC is undergoing an evolution with multiple new agents on the horizon, from immune modulators to vaccines to novel antiandrogens. The development of next generation imaging with PSMA PET, the assessment of germline and somatic genetic alterations and the ability to target therapies based on these precision-based strategies gives rise to great optimism as we look to the future in treating men. In addition, use of approved agents is being trialed in earlier stages of the disease state. This course delivers AUA Guideline updates, keeping clinicians abreast of this rapidly changing landscape of APC.