Metastatic Castrate-Sensitive Prostate Cancer: Comparison
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Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Approximately one-third of all prostate cancers are metastatic at the time of diagnosis (synchronous) or recur (metachronous) following definitive treatment. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer

  • prostate cancer
  • ARAT
  • androgen receptor axis-targeted drugs
  • docetaxel
  • BRCA1/2
  • breast cancer gene 1/2

1. Introduction

Prostate cancer is one of the most frequently diagnosed neoplasms in men. In 2022, nearly 24,600 Canadians were diagnosed with prostate cancer, representing 20% of all new cancer cases in men. Moreover, 4600 Canadian men died from prostate cancer, representing 10% of all cancer deaths in males. The death rate for prostate cancer has been declining since 1994, reflecting improved treatment [1]. Approximately one-third of all prostate cancers are metastatic at the time of diagnosis (synchronous) or recur (metachronous) following definitive treatment. The main therapeutic strategy for metastatic prostate cancer involves androgen deprivation therapy (ADT) [1][2]; however, most patients will develop lethal castration resistance [3]. In the past decade, new androgen receptor axis-targeted (ARAT) drugs, namely abiraterone acetate plus prednisone (henceforth abiraterone), enzalutamide, apalutamide and darolutamide have been assessed across different stages of prostate cancer [4][5][6][7][8][9][10][11]. Their application early in the disease trajectory has resulted in both improved survival and maintenance of quality of life (QoL) in men with non-metastatic and metastatic prostate cancer among all age groups [12][13][14][15][16].

2. Metastatic Castrate-Sensitive Prostate Cancer

The benefits of surgical or pharmacologic castration with androgen deprivation therapy (ADT) were established in 1941 [12]. Metastatic prostate cancer was consequently considered to be either castration-sensitive or -resistant, referring to an early state of the disease susceptible to castration and a later state that is no longer vulnerable to testosterone suppression, respectively. A paradigm shift occurred in 2015 with the advent of combination therapy, so-called “intensification beyond androgen deprivation therapy”. Improved overall survival (OS) was demonstrated in studies assessing the efficacy of adding docetaxel or androgen biosynthesis inhibition with abiraterone acetate and prednisone along with blockade of the androgen receptor with enzalutamide or apalutamide. These data will be summarized below.

A. Cytotoxic Drug Therapy

The addition of docetaxel was the first agent to demonstrate favorable efficacy in this setting. When compared to ADT alone, docetaxel administered over six cycles every 21-days initiated within the first 120 days of ADT in patients with de novo metastatic disease was associated with improved median OS in patients with high-volume disease (median OS 44 months with combination vs 32.2 months with ADT alone). High-volume disease was defined as the presence of visceral metastasis or at least four bone metastases of which at least one had to be present outside of the spine and pelvis [13]. All other disease states with metastases that do not meet these criteria are referred to as low-volume. In 2016, another trial confirmed these results, with an improvement in median OS of 10 months [14] (Figure 1 and Figure 2).
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Figure 1. Proposed overview for the management of low-volume or -risk metastatic castration-sensitive prostate cancer (CSPC). High risk definition (from LATITUDE) [7]: at least 2 of the following: ≥3 bone metastases, visceral metastases, Gleason score ≥8. High volume definition (from CHAARTED) [13]: at least 1 of the following: ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis or visceral metastases. * = Data for the use of docetaxel in low-volume disease is limited, see text for further discussion.
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Figure 2. Proposed overview for the management of high-volume or risk metastatic castration-sensitive prostate cancer (CSPC). High risk definition (from LATITUDE) [7]: at least 2 of the following: ≥3 bone metastases, visceral metastases, Gleason score ≥8. High volume definition (from CHAARTED) [13]: at least 1 of the following: ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis or visceral metastases. * = Rezvilutamide where available.

B. Oral Hormonal Agents and ADT (“Doublet-Therapy”)

Abiraterone acetate demonstrated an OS benefit when administered until disease progression in patients with de novo metastatic disease and high-risk features defined as two of the following: Gleason score 8 or higher, visceral disease and at least three bone metastases. Radiographic progression free survival (rPFS) was 33 months in the abiraterone group versus 14.8 months with placebo. The reduction in the risk of radiologic progression was 53%. Median OS was 53.3 months in patients receiving abiraterone versus 36.5 months in patients receiving placebo, with a relative improvement in OS of 33% [7]. Enzalutamide was associated with improved survival in patients with de novo metastatic disease in the ARCHES trial [16]. The primary endpoint, median rPFS, was not reached with enzalutamide plus ADT versus 19 months with placebo plus ADT, with a significant reduction in risk of 61%. The risk reduction for death in the final report was significantly decreased by 33%. In the ENZAMET trial, patients randomized to ADT and enzalutamide versus ADT and non-steroidal antiandrogens demonstrated a survival advantage that favored enzalutamide [17][18]. Median OS was not reached after a median follow-up period of 44 months in ARCHES and 68 months in ENZAMET. A subgroup analysis of ENZAMET patients who had received prior docetaxel chemotherapy did not demonstrate any incremental OS benefit. Apalutamide was assessed in the TITAN trial, which randomized patients with mCSPC to ADT plus apalutamide versus placebo plus ADT and primary endpoint of rPFS. In this study, about 10% of patients had received prior docetaxel chemotherapy. Furthermore, about one-third of patients did not have high-volume disease using the CHAARTED definition. Investigators showed that rPFS was improved by 52% in the apalutamide group whereas OS was improved by 35% and median OS was not reached for the apalutamide group versus 52.2 months in patients receiving ADT alone [19][20]. A novel second-generation drug unavailable in North America is rezvilutamide. This compound’s efficacy and safety were assessed in the phase III CHART trial, which enrolled men with high-volume mCSPC who had never received chemotherapy and randomized them to ADT plus rezvilutamide versus ADT plus bicalutamide. Notably, 90% of patients were Chinese. Improved rPFS was demonstrated with rezvilutamide compared to bicalutamide (median rPFS not reached) versus 25.1 months (HR 0.44 [95% CI 0.33–0.58); p < 0.0001). Rezvilutamide significantly improved overall survival compared to bicalutamide (HR 0.58 (95% CI 0.44–0.77); p = 0.0001), whereas median OS was not reached for either arm at the time of publication. The most common grade ≥3 adverse events were hypertension (8% versus 7%), hypertriglyceridemia (7% versus 2%), weight gain (6% versus 4%), anemia (4% versus 5%) and hypokalemia (3% versus 1%), with rezvilutamide compared to bicalutamide, respectively [21].

C. Docetaxel with Oral Hormonal Agents and ADT (“Triplet-Therapy”)

As of 2024, none of these strategies have been formally compared to one another in a clinical trial and are considered alternatives. The most recent development in this setting is the combination of ADT, docetaxel chemotherapy and either abiraterone or darolutamide.

i. Darolutamide with Docetaxel and ADT

ARASENS was a phase III trial that assessed the efficacy and safety of darolutamide in patients with mCSPC who were candidates for ADT and docetaxel. Participants were randomized to ADT and six cycles of docetaxel and darolutamide versus ADT, docetaxel and placebo. The primary endpoint was OS and was not reached for the darolutamide group versus 48.9 months for placebo, with a significant improvement in the risk of death of 32%. The study did not stratify patients by risk or volume of disease [22]. A subsequent report assessed therapeutic benefits in all volume and risk settings, and concluded that patients with high-volume mCSPC were most likely to profit from triplet therapy whereas patients with except for low-volume mCSPC were most likely to benefit from ADT plus androgen receptor-targeted agents.disease [23].

ii. Abiraterone with Docetaxel and ADT

Abiraterone was assessed in the PEACE-1 trial which compared ADT, docetaxel and abiraterone vs ADT and docetaxel in patients with de novo metastatic hormone sensitive prostate cancer. Patients were stratified by disease volume as per the CHAARTED criteria mentioned above. Participants with high-volume disease had significant improvement in OS (median 61 vs. 42 months), whereas patients with low-volume did not [24]. Achievement of undetectable 8-month PSA after initiation of ADT with abiraterone and docetaxel predicted improvement in rPFS and OS [25].

iii. Triplet Therapy Data Limitations

Given the lack of available head-to-head comparisons between triplet (darolutamide or abiraterone with docetaxel and ADT) and doublet strategies (ARAT and ADT), the use of either approach is currently accepted as a reasonable evidence-based alternative. In all cases, a careful discussion of the available evidence is recommended to enable patients to make well-informed decisions. A systematic review of all the main phase III trials indirectly compared these different approaches and concluded that the best OS and radiologic PFS occurred with abiraterone-based triplet therapy vs. ADT alone, notwithstanding study limitations. However, this is still an indirect comparison of clinical trials with different methodologies and disease characteristics such as high and low volume and/or risk, and the information must therefore be interpreted with caution [23].

D. Radiotherapy for Low-Volume Disease

The role of radiotherapy in newly diagnosed metastatic prostate cancer was investigated in the STAMPEDE trial, which compared systemic therapy alone to systemic therapy plus radiotherapy to the prostate using 55 Gy in 20 fractions or 36 Gy in 6 fractions. Systemic therapy consisted of lifelong ADT with or without docetaxel (18%). Metastatic burden was defined per the CHAARTED criteria above. In patients with low-burden disease, but not high-burden, radiotherapy improved 5-year overall survival (HR 0.64, 95% CI 0.52–0.79; p < 0.001), failure-free survival and progression free survival [26][27]. These data suggest that prostate radiotherapy should be recommended as a standard of care for these men.

3. Putting It All Together: Practical Recommendations for Clinicians

Most men with metastatic prostate cancer are candidates for intensification above androgen deprivation. Important considerations when prescribing and supervising ARAT agents include understanding efficacy (summarized above), addressing relevant toxicities, managing drug–drug interactions, determining progressive disease and understanding unique considerations for older adults (Figure 3). This section introduces the latter four concepts. In all cases, the standard recommendation is to monitor drug therapy on a continuous basis.
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Figure 3. Proposed conceptual framework for the management of metastatic prostate cancer. DDI’s: drug–drug interactions.
 A. Addressing Relevant Toxicities Thyroid dysfunction may be observed at a higher frequency in patients receiving apalutamide but is uncommonly clinically significant. In TITAN, 6.5% of participants had all-grade (non-severe) hypothyroidism, autoimmune thyroiditis or blood thyrotropin elevation relative to 1.1% in the placebo group [20]. The authors recommend every 3–6-month serum thyrotropin, free thyroxine and free triiodothyronine in patients receiving apalutamide and optimization of clinically abnormal levels with oral thyroid replacement based on standard targets. Next, apalutamide may be associated with early-onset (within 6 months) skin rash, as described in TITAN [19]. Cutaneous reactions tend to be mild and generally self limiting and can range from a maculopapular rash to severe toxic skin eruptions. In certain circumstances, temporary withdrawal of the offending agent, initiation of topical corticosteroids and referral to dermatology are necessary. For severe drug eruptions, however, withdrawal of the inciting agent along with initiation of systemic corticosteroids with a slow tapering schedule is recommended. Re-challenge with the same agent should then be avoided. B. Managing Drug–Drug Interactions Apalutamide, enzalutamide and darolutamide are associated with multiple drug–drug interactions that are highly relevant to clinical practice (the Canadian Urological Association 2023 tool card can be found at https://www.cua.org/sites/default/files/Flipbooks/CPD/ddi2023/index.html). Consider the following examples: apalutamide may decrease serum level of rivaroxaban through induction of CYP3A4, thereby decreasing the efficacy of the anticoagulant and its protective effects against cerebrovascular accidents [28]. Therefore, it would be reasonable to consider switching from rivaroxaban to edoxaban to minimize such risk. Similarly, enzalutamide may decrease serum concentrations of both atorvastatin and simvastatin due to potent induction of CYP3A4. Consequently, higher doses of atorvastatin may be necessary to achieve lipid goals [29]. A thorough review of patients’ prescriptions is essential to maximize the efficacy of prostate cancer therapy and minimize associated harms related to concomitant co-morbidities. C. Determining Progressive Disease When managing men with metastatic prostate cancer, it is imperative to re-engage specialists in genitourinary oncology to confirm disease progression and discuss next steps. Furthermore, the identification of prostate cancers that harbor deleterious mutations in homologous recombination repair is highly relevant given the availability of novel agents that target PARP, as discussed above. The Prostate Cancer Clinical Trials Working Group-3 (PCWG-3) has specified three key features, of which any two are required to establish progressive disease: (1) symptomatic progression, (2) radiographic progression and (3) biochemical progression [30]. Patients should be referred back to the treating medical oncologist or urologist if intolerable adverse events result from treatment in spite of dose adjustments, re-staging imaging confirms new lesions or meets the standard definition for disease progression [68], two or more consecutive increases in PSA are detected or if cancer-related symptoms arise regardless of PSA level. D. Notable Considerations in Older Adults The International Society of Geriatric Oncology recommends classifying men older than 75 years with prostate cancer as healthy, vulnerable or frail and subsequently tailoring treatment decisions based on individual health status instead of chronological age [31]. Older cancer survivors may have cognitive deficits which negatively affect quality of life and daily functioning and are therefore important concerns when selecting appropriate drug therapy in this vulnerable group [32]. Central nervous system blockade of the androgen pathway may lead to adverse consequences on cognitive function and emotional wellbeing requiring prompt identification and management. A number of reports have addressed the cognitive and psychological effects of ADT and early generation androgen receptor antagonists [33][34][35][36]. In a recent systematic review of 15 randomized clinical trials in nearly 9000 men with metastatic prostate cancer addressing cognition and depression effects of ARAT agents, depression was found to be more commonly assessed than cognition in men receiving ARATs [37]. Self-reported depression measures favored abiraterone over enzalutamide and both abiraterone and enzalutamide over placebo but not necessarily over first-generation antiandrogens. Furthermore, abiraterone may improve short-term emotional functioning relative to enzalutamide. The magnitude and clinical importance of its effects on cognition and depression were unclear. Data evaluating apalutamide and darolutamide were not available [37]. The authors believe that it is reasonable to consider annual cognition and depression assessment using validated screening tools such as the Montreal Cognitive Assessment test [38] and Patient Health Questionnaire-9 [39]. Psychosocial oncology supports are expected to improve and maintain quality of life for older adults meeting the criteria for cognitive impairment or depression in order to optimize adherence and oncologic outcomes for this vulnerable cohort.

4. Conclusions

Promising new therapeutic strategies for men with metastatic prostate cancer are improving outcomes and have manageable toxicity profiles. Clinicians are encouraged to develop their knowledge and experience using androgen receptor axis-targeted agents as well as managing relevant toxicities in collaboration with medical oncologists. Recommendations from the Canadian Urologic Association, American Urologic Association and European Society of Medical Oncology are available online and are useful resources. Collaborative efforts that include multi-disciplinary cancer clinicians are needed to optimize care for men with incurable prostate cancer.

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