Learning Objective

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

• Assess current approaches and explore new strategies for clinical management of advanced prostate cancer.

The management of advanced prostate cancer (APC) has undergone some major changes in recent years from patient evaluation to treatment secondary to the addition of many new treatments to our toolbox by way of recent genetics and clinical trials. Although only 6% of our prostate cancer patients will initially present with distant disease, we know that the implications on quality of life and prognosis are great.

Figure. Treatment checklist.¹⁵

Evaluation

A thorough patient evaluation can have impacts on screening, treatment choice and initiation of lifestyle modification. We need to consider ethnicity, family history of cancer or genetic mutations, body mass index, tobacco use, diet and biopsy/imaging findings.

Recent advances in genetics highlight the importance of proper patient evaluation and screening. This will continue to evolve as guidelines and clinical pathways catch up with the data. Finding out about germline mutations or somatic mutations is crucial for our high-risk patients because these patients can now benefit from more targeted treatments as well as provide risk assessment for family members (germline).

Germline testing is easily sampled (swab or tissue) and is recommended for high-risk or metastatic disease, but also patients with lower risk but with strong family history or adverse pathological features such as intraductal/cribriform cell types. Somatic mutation testing is performed with tissue biopsy and can help with treatment decision making. All in all, 20% will have additional treatment options as a result of testing; 10% will have inherited or germline mutations with BRCA2 being the most common, ∼20%–25% will have homologous recombination deficiencies and will benefit from PARP inhibitors, and 5%–7% of patients will have mismatch repair deficiencies/microsatellite disabilities and will benefit from our immune checkpoint inhibitors.^1–3

Imaging evaluation is newly expanding as well. Currently our definitions of metastatic disease use traditional imaging modalities, but as magnetic resonance imaging and prostate specific membrane antigen positron emission tomography become more readily available and help us to better characterize the extent of disease after biochemical recurrence these guidelines will potentially shift and may result in reclassification of patients beyond M0.⁴

Treatment

For over 60 years our treatment option for our patients with APC was androgen deprivation therapy (ADT) and ADT alone, and in the last 15 years genetics and clinical trials have directly resulted in several lines of Food and Drug Administration approved systemic therapies that are indicated for various disease states (see figure).

Disease States

Biochemical Recurrence: Biochemical recurrence is defined as a detectable prostate specific antigen (PSA) that rises on 2 consecutive measurements or does not fall to undetectable levels. Unfortunately, about 20%–30% of our patients treated with intent to cure will fall into this category. Our treatment options for these patients start with observation alone and continue with conventional as well as newer options. This decision is based on risk derived from age and comorbidities, pathological features, time to PSA recurrence and PSA velocity. As more men are afforded the opportunity for treatment long before they develop distant metastasis, we must weigh long-term survival vs treatment effects/quality of life issues as we trend toward younger, healthier men in this category.

It is well-known that ADT has many long-term considerations and/or complications and we must especially as Advanced Practice Providers remain diligent when it comes to monitoring by way of blood work, bone density, cardiac monitoring and adherence to appointments; prevention/mediation by way of encouraging/facilitating smoking cessation, decreased alcohol consumption, vitamin supplementation, heart healthy diet, brain training and maybe most importantly a continuous exercise regimen. Patient support services/survivorship programs are crucial for these patients.

Metastatic Hormone Sensitive Prostate Cancer: These patients can be asymptomatic or minimally symptomatic. Our treatments here include ADT alone or with the addition of a next generation oral anti-androgen (abiraterone, enzalutamide, apalutamide, darolutamide) or systemic chemotherapeutic agents (docetaxel). Data from the LATITUDE, STAMPEDE and ARCHES trials have made combination therapy standard of care for these patients. Our choices are determined by prognostic indicators as well as side effect profiles. ADT alone is still appropriate for patients with poor cardiac function or significant comorbidities. Abiraterone must be given with prednisone because of increased mineralocorticoid activity. Prednisone is not necessary with enzalutamide, apalutamide or darolutamide but these agents carry the risk of seizures and multiple drug interactions. We consider addition of chemotherapy in the patient with high-volume (visceral metastasis and/or at least 4 bone lesions, including at least 1 distant bony lesion) hormone sensitive metastatic prostate cancer.^5–8

Nonmetastatic Castration Resistant Prostate Cancer: Nonmetastatic castration resistant prostate cancer is defined as PSA progression without evidence of metastatic disease in patients receiving hormonal therapy with castrate levels of testosterone. This definition currently utilizes conventional imaging and not new modalities such as prostate specific membrane antigen positron emission tomography. This subset of patients may be largely impacted in the coming years as our imaging improves.

The SPARTAN, PROSPER and ARAMIS studies found that treatment with ADT plus abiraterone, enzalutamide or darolutamide increased the time to metastasis, and the earlier you add these medications to ADT the longer men live, no matter what treatment they get later.^9–11 Chemotherapy and immunotherapy currently do not have a role in the management of patients with nonmetastatic castration resistant prostate cancer.

Metastatic Castration Resistant Prostate Cancer: Metastatic castration resistant prostate cancer is defined as PSA progression with the development of new metastasis despite castration levels (T<50) of testosterone. Our treatment toolbox for these patients has many additions over the last few years. We now have the above treatments as well as immunotherapy, radium and targeted therapies. When talking about this subset of patients and deciding on treatment we want to apply 3 questions: Are they symptomatic? Have they received chemotherapy? And What is their performance status? The paradigms are shifting in terms of when to add to ADT and focus on timing and layering or sequencing of these newer agents with targeted treatments. We know that chemotherapy works best for patients with high-volume disease. Sipuleucel T is our immunotherapeutic option. The ideal patient for sipuleucel T is asymptomatic or minimally symptomatic with no liver metastasis. It is of note with this medication to counsel patients as we often do not see a decline in PSA or improvement in scans despite survival benefit. All metastatic castration resistant prostate cancer patients should receive genetic testing to determine if they will benefit from PARP inhibitors. These are for patients with homologous recombination genes such as BRCA, ATM and CHEK2. Olaparib is offered to patients with a somatic or germline DNA repair gene mutation after treatment with an oral androgen receptor targeted agent.¹² Rucaparib is offered to patients with a germline or somatic BRCA1 or BRCA2 after treatment with an oral androgen receptor targeted agent and taxane-based chemotherapy.¹³ Radium-223 is used to target bone lesions and only used if no visceral metastasis. Of note, this should not be used with abiraterone secondary to increased risk of fracture. Checkpoint immunotherapy (pembrolizumab/nivolumab) is one of our newer options for targeted treatment for patients with deficient DNA mismatch repair genes.¹⁴

AUA Index Patients

Asymptomatic, Good Performance Status: These patients have a rising PSA, documented metastasis on imaging, no prior chemotherapy and are asymptomatic, not requiring pain medication. Here we will offer a next generation oral hormone, chemotherapy or sipuleucel T. This is the ideal patient for this immunotherapeutic agent.

Symptomatic, Good Performance Status: Patients are included in this category if they have a rising PSA and documented metastasis on imaging but also have symptoms attributable to their cancer. Treatment options here include docetaxel, abiraterone and enzalutamide, as well as radium if pain secondary to disease burden. Patient selection is important here as chemotherapy shows maximal benefit in patients with high volume disease.

Symptomatic, Poor Performance Status: Treatment options are abiraterone, enzalutamide, docetaxel and radium-223 if performance status parallels disease.

Much of these guidelines are extrapolated or based on expert advice secondary to trial limitations but it is important to consider treatment for these patients especially if their poor performance status is attributable to their disease or disease burden. This is also important as we are seeing younger patients in this category secondary to younger patient trends.

Symptomatic, Good Performance, Prior Docetaxel: As patients are now receiving earlier ADT and subsequently earlier becoming castration resistant and thereby offered docetaxel there remains a subset of patients who still have good performance status and can be offered immunotherapy. These patients will benefit most from layering with abiraterone, cabazitaxel, enzalutamide, docetaxel and radium.

Symptomatic, Poor Performance, Prior Docetaxel: Care should be focused on palliation for these patients but select patients can benefit from next generation oral hormones or targeted radionucleide.

Over the last decade, we have seen considerable advances in the biological understanding of APC resulting in the development of novel agents and treatment paradigms. Unfortunately, despite these significant strides APC remains a fatal disease, highlighting the need to continue to improve the care of these patients. Screening and early diagnosis are paramount as they can lead to individualized treatment strategies for patients with APC.

Optimized treatment of men with APC requires a multidisciplinary team to follow side effects, enroll in trials, ensure adherence to appointments, and maintain overall physical and mental health. As Advanced Practice Providers, we are frequently the cornerstone of this treatment team. Through shared decision making and patient education, we can make a meaningful impact on these patients’ overall health and maximize their quality of life.