The Treatment of Metastatic, Hormone-Sensitive Prostatic Carcinoma

Background: For many years, the standard treatment of metastatic, hormone-sensitive prostatic carcinoma (mHSPC) was androgen deprivation therapy (ADT) alone. By lowering the testosterone level into the castration range, ADT deprives the tumor of a key growth factor.

Methods: For this article, we evaluated the treatment recommendations contained in national and international guidelines (German S3 guidelines and those of the European Society for Medical Oncology [ESMO], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN]), as well as pertinent publications revealed by a PubMed search and the congress abstracts of the ESMO and of the American Society of Clinical Oncology [ASCO].

Results: The past few years have witnessed fundamental changes in the treatment of mHSPC. Treatment intensification with docetaxel or with the new drugs directed against the androgen receptor signal pathway (abiraterone, apalutamide and enzalutamide) has been found to lower mortality by 19–40% and is now an integral component of first-line therapy. Relevant new findings have also been obtained with threefold combinations of ADT, docetaxel, and abiraterone or darolutamide. For patients with a light tumor burden, local radiotherapy of the primary tumor improves the probability of survival at 3 years by 8% (45.4 versus 49.1 months, difference 3.6 months; 95% confidence interval, 1.0 to 6.2 months).

Conclusion: The treatment of mHSPC is constantly changing. Phase III trials that are now in the recruitment stage, as well as our continually improving understanding of the underlying molecular-pathological mechanisms, will be altering the treatment landscape still further in the years to come.

Prostate cancer (PCa) is the most common cancer in men. The Robert Koch Institute estimates that 70 000 new cases of the disease will be diagnosed this calendar year in Germany alone (1).

However, patients with advanced PCa may or may not be symptomatic. Local signs and symptoms, which may occur in varying severity, include difficulty urinating culminating in urinary retention, erectile dysfunction and metastatic pain, especially in the spine and pelvis (2). An abnormal digital rectal examination (DRE) finding may be an important clue. However, since DRE findings are strongly influenced by the site and size of the tumor, in about one third of patients with normal DRE a tumor is later detected. Increased prostate-specific antigen (PSA) levels may indicate the presence of cancer and thus require further diagnostic workup by a specialist. Density, rate of rise, doubling time as well as the proportion of free PSA are factors that increase the strength of evidence. Elevated bone-specific alkaline phosphatase (BAP) and serum calcium levels may be signs of bone metastasis.

The 10-year relative survival rate of patients with metastatic PCa is approximately 15% (3). Early in the disease process, androgens are the critical driver of tumor growth. Pharmacological androgen deprivation therapy (ADT) is a key component of management in this setting, with more than 90% of patients experiencing a reduction in tumor growth in response to ADT. Hence, this form of PCa is referred to as a hormone-sensitive PCa (HSPC). In case of progression of tumor growth despite sufficiently suppressed testosterone levels, the disease state is referred to as a castration-resistant PCa (CRPC).

The aim of this review is to provide an overview of the various treatment options available in the hormone-sensitive setting of advanced prostate cancer as well as decision-making support for everyday clinical management.

Learning objectives

After reading this article, the reader should be able to

• define metastatic prostate cancer and classify it according to the known risk scores.
• specify the risk group-dependent, guideline-recommended systemic treatment options
• put the role of radiation therapy and surgery in the metastatic setting in context
• understand important other aspects along the path to the personalized treatment decision

Classification of mHSPC based on timing and extent of metastasis and risk factors

Metastatic hormone-sensitive prostate cancer (mHSPC) may present at diagnosis as a primary metastatic (synchronous) disease or as a recurrence after local treatment (metachronous disease). The prognosis of synchronous metastatic PCa is considerably less favorable with a significantly shorter time to transition to resistance (372 versus 1613 days; p<0.001) and a significantly shorter median overall survival (OS) of only 6.2 years compared to 11.6 years in metachronous metastatic patients (4, 5). Additionally, tumor extension has a significant impact on the course of the disease. For this reason, it is included in the various risk classifications which were defined in the CHAARTED and LATITUDE studies (Box).

Box

Definition of tumor burden and high-risk constellation in clinical studies

In terms of prognosis, patients are thus split into two groups:

• Primary metastatic patients with high tumor burden and consequently poor prognosis, often experiencing an aggressive disease course
• Patients with recurrence after previous treatment of the primary tumor and few metastases with often prolonged disease course.

The remaining patients are classified somewhere between these two patient populations.

Conventional imaging and PSMA PET/CT for determining the extent of spread

Conventional imaging with computed tomography (CT) and skeletal scintigraphy remains the recommended standard for determining the extent of cancer spread (2).

The risk classifications described above and the study results presented in the following are based on these imaging techniques. Nevertheless, the use of more advanced imaging techniques is also increasing in mHSPC. As an example, positron emission tomography (PET) can be used to visualize prostate-specific membrane antigen (PSMA) on cell surfaces. This protein is primarily expressed by PCa cells.

Hence, PET enables early detection of metastases, which would not be possible using conventional imaging. As a consequence, patients are increasingly diagnosed at advanced stages of the disease or assigned to higher risk groups (eCase report) (8).

National and international working groups are developing proposals on how to deal with this phenomenon referred to as stage migration.

Today, PSMA PET/CT is already of key importance for addressing specific questions, for example prior to the initiation of metastasis-directed therapy (MDT) as an individualized treatment concept (S3-level clinical practice guideline) (2).

Magnetic resonance imaging (MRI) can be relevant to precisely determine the extent of the primary tumor or, for example, of an intraspinal space-occupying lesion; however, it is not the standard imaging modality in the metastatic setting.

For further information, please refer to the review article titled ”Imaging of Prostate Cancer“ in the ‚Deutsches Ärzteblatt’ (9).

Androgen deprivation therapy as a key element of treatment

Androgen deprivation therapy (ADT) results in chemical castration. As a monotherapy, it was the standard of care in the first-line treatment of mHSPC for many decades. ADT alone achieved disease control over a period of 18 to 24 months in >90% of patients (10). Today, ADT is the backbone of all systemic therapies of mHSPC and it is continued even in case of a change in therapy.

In everyday clinical practice. GnRH agonists are commonly used for ADT, owing to the fact that they are usually easier to administer and better tolerated by patients. A prospective randomized phase III study and meta-analyses, however, point to a lower rate of cardiovascular events with GnRH antagonist treatment, especially in patients with relevant pre-existing conditions (11, 12). Besides GnRH antagonists, surgical castration is used for androgen deprivation therapy, but only rarely.

Increasing life expectancy through treatment intensification

In view of the treatment successes achieved in the castration-resistant stage with taxane-based chemotherapy and new drugs targeting the androgen-receptor (AR) pathway—referred to as new hormonal agents (NHAs)—, it was only logical to also evaluate their effectiveness in patients with mHSPC—with success.

Key aspects of the pivotal studies on the various options for treatment intensification in the hormone-sensitive setting are discussed below. The results are both reviewed and weighed up in the section on treatment recommendations.

Treatment intensification with docetaxel

Docetaxel was the first substance to trigger a paradigm shift in the management of mHSPC. The addition of this microtubule stabilizer to the standard of care (SOC) with ADT was evaluated in two randomized phase III studies (Table 1) (13, 14). Using this approach, the CHAARTED trial was the first to demonstrate improvement in median overall survival by more than 10 months over a total period of 50 months (13). It also found that patients with high tumor volume benefited the most (Box). The STAMPEDE trial (arm C and E), published somewhat later, confirmed the results of the CHAARTED trial overall, but the benefit was independent of the magnitude of the tumor burden. Thus, in the German S3-level clinical practice guidelines (S3GLs) there is a ‘should’ recommendation for patients with high tumor volume and a ‘may’ recommendation for patients with low tumor volume for the addition of docetaxel to ADT (2, 15). Higher-grade adverse events (CTC AE ≥ G3) occurred in 29% and 52% of patients in the CHAARTED trial and STAMPEDE trial, respectively. Febrile neutropenia, in particular, is a potentially life-threatening adverse event experienced by 6% and 15% of patients, respectively. In everyday clinical practice, the early use of granulocyte colony-stimulating factor (G-CSF) can help to prevent this complication. The side effects of chemotherapy are usually limited to the period of administration and subside after treatment has been completed. Peripheral polyneuropathy may be an exception to this general rule; however, peripheral polyneuropathy was a rather rare severe adverse event in both studies (1% and 3%, respectively) (13, 14).

Table 1

Randomized phase III studies on hormonal chemotherapy for metastatic hormone-sensitive prostate cancer

Treatment intensification with drugs targeting the androgen receptor signaling pathway

The new drugs targeting the androgen receptor (AR) signaling pathway are designed to further suppress the effect of androgens on prostate cancer cell growth beyond chemical castration with ADT. This can be achieved by inhibiting the synthesis of precursors (abiraterone) or by blocking the AR receptor and signaling pathway (apalutamide, darolutamide, enzalutamide).

Various phase III studies have evaluated treatment intensification with NHAs.

Initially, treatment with ADT alone was the standard of care. Data on hormonal chemotherapy published during the recruitment phase of these trials led to the adaptation of the studies, enabling either docetaxel pre-treatment or parallel administration (Table 1).

In addition, the different inclusion criteria resulted in relevant differences between the patient populations studied.

As the first NHA, abiraterone was evaluated in combination with prednisone in the LATITUDE trial in patients with synchronous metastatic HSPC and high-risk constellation (Table 1), demonstrating a significant and clinically relevant prolongation of OS through therapy intensification (7). Similar to what had already been shown for docetaxel, the STAMPEDE trial (arm G) also confirmed the results for intensified hormone therapy. However, this trial allowed the inclusion of patients irrespective of tumor extension and risk constellation. Post-hoc analyses demonstrated an advantage for abiraterone, irrespective of the subgroup. Nevertheless, the approval of abiraterone for the treatment of mHSPC was limited to patients with synchronous metastatic HSPC with high-risk features according to LATITUDE criteria (Table 1).

The TITAN trial evaluated the efficacy of apalutamide in addition to the standard of care in patients with metastatic hormone-sensitive prostate cancer. TITAN addressed an all-comer population, i.e. study inclusion was independent of the timing of metastasis (synchronous/metachronous), tumor extension or Gleason score. The standard treatment was ADT alone; 11% of patients in both treatment arms received in addition docetaxel prior to randomization. The final analysis showed a 35% reduction in risk of death. After adjusting for patients who received apalutamide after unblinding of the study and crossing-over to the test arm, this advantage increased to 48% (16).

Similar all-comer populations were evaluated in the two studies on enzalutamide—the ARCHES and ENZAMET trials. The design of the ARCHES trial (17) is similar to that of the TITAN trial; nearly 18% of patients received pre-treatment with docetaxel and ADT was the treatment standard. The final analysis of the study was presented at the Congress of the European Society of Medical Oncology (ESMO) last year. Despite the cross-over of approximately 31% of control arm patients, treatment intensification by adding enzalutamide improved overall survival by 34%. In the ENZAMET trial, a non-steroidal antiandrogen was administered in addition to ADT in the control arm for complete androgen blockade and compared to ADT plus enzalutamide. In 45% of patients in each study arm, parallel docetaxel administration in addition to hormone therapy was planned. In this study too, enzalutamide led to a significant improvement in overall survival in the total patient cohort (HR 0.67; 95% confidence interval (CI]: [0.52; 0.86]). In contrast, the added benefit of concomitant docetaxel treatment is less clear (18).

Based on these study data, abiraterone, apalutamide and enzalutamide each received a ‘should recommendation’ for their use in the treatment of mHSPC, with this being limited to the approval criteria in the case of abiraterone (at least two of three criteria for high-risk constellation, see Box) (2). Acute tolerability of intensified hormonal therapy with NHA is usually better than that of hormonal chemotherapy. Substance-specific differences can help with the choice of NHA. Here, we would like to refer to their respective Summaries of Product Characteristics (SPCs).

Triple combination therapy as a recent treatment approach

Given that combination therapies with ADT and docetaxel or new androgen receptor-targeted drugs have long become the standard of care, two randomized, multicenter Phase III trials presented data on triple combination therapy for the first time last year.

The first was the PEACE-1 study on patients with synchronous metastatic HSPC, which was conducted by the European Prostate Cancer Consortium independent of the pharmaceutical industry. The 4-arm design of the study is complex. Only the results for the triple combination with ADT, docetaxel and abiraterone/prednisolone compared to hormonal chemotherapy with ADT and docetaxel are presented in the following. There was in fact a significant prolongation of radiographic progression-free survival by 2.5 years with further treatment intensification with abiraterone (HR 0.5; 95% CI: [0.40; 0.62]; p<0.0001) as well as a 25% reduction in the risk of death (HR 0.75; 95% CI: [0.59; 0.95]; p = 0.017). With a survival advantage of 1.5 years for the triple combination therapy compared with hormone chemotherapy alone, this benefit was particularly striking in patients with high tumor burden (HR 0.72; 95% CI: [0.55; 0.95]; p = 0.019). Presently, the significance of triple combination therapy is still unclear in patients with low tumor volume (0.83; 95% CI: [0.50; 1.38]; p = 0.66) (Table 3) (23).

Table 2

Key data from the PEACE-1 and ARASENS triple therapy trials

In the ARASENS trial, hormonal chemotherapy was intensified with darolutamide. This polar AR inhibitor has a different chemical structure and thus does not readily cross the blood-cerebrospinal fluid barrier. This seems to translate into a particularly favorable side-effect profile (24).

The ARASENS trial also reached its primary endpoint by lowering the risk of death by 32.5% (HR 0.68; 95% CI: [0.57; 0.80]; p<0.001). The survival benefit resulting from the addition of darolutamide was consistent across all subgroups (24). Similar to the PEACE-1 study, many patients had a high-risk constellation at study inclusion. An analysis of the influence of tumor burden on treatment outcome is not yet available. The addition of darolutamide barely changed the side effect profile (adverse side-effects ≥ grade 3: triple combination 70.2%; hormonal chemotherapy 67.5%). Only the number of patients with arterial hypertension was measurably higher (6.4% versus 3.2%).

Both studies have been criticized for the lack of a comparison arm receiving a combination of the respective AR signaling pathway-targeted drug and ADT. At the time these studies were designed, this treatment option had not yet become the standard of care and was therefore not taken into account. Consequently, it is difficult to make a statement about the advantage of triple combination therapy in comparison to intensified hormone therapy.

Local prostate treatment

Until a few years ago, therapy of the primary tumor in patients with mHSPC was only performed to either treat or prevent local complications.

Retrospective analyses were followed by two prospective, randomized studies and one meta-analysis (25, 26, 27). In the H arm of the STAMPEDE trial, 2061 mHSPC patients were randomized. These patients received either systemic therapy (ADT ± docetaxel) alone or in addition hypofractionated prostate radiotherapy. This additional prostate treatment led to a significant improvement in the time to treatment failure by 9% (23% versus 32%; HR 0.76. 95% CI: 0.68; 0.84]; p<0.0001). However, there was no difference in median overall survival. For patients with low metastatic burden, on the other hand, a significant benefit for overall survival and prostate cancer-specific survival was found (Table 1) (6, 13, 25).

In the smaller HORRAD trial. 432 patients with mHSPC (26) received ADT plus prostate radiotherapy or ADT alone. Patients were included irrespective of tumor extension and lymph node involvement if they had bone metastases. In this study, no difference for overall survival or PSA relapse-free survival was found. In addition, unlike the STAMPEDE trial, no subgroup was identified in which patients would have benefited from radiotherapy. This also applied to patients with a low number of metastases.

An analysis was performed for the two studies STAMPEDE and HORRAD discussed above (26). The primary endpoints were the same as those in the two studies. As expected, overall survival of the pooled cohort was not significantly improved by additional prostate radiotherapy (p = 0.238), in contrast to biochemical progression and event-free survival (each p<0.001). In order to analyze the impact of the number of metastases, an evaluation of patients with low (< 5) or high tumor burden (≥ 5 metastases) was performed. If less than five metastases were detected, prostate radiotherapy led to a significant survival benefit of 7% (70% versus 77%; p = 0.007).

Based on these study results, the current S3-level clinical practice guideline (28) and a recent consensus publication (29) recommend prostate radiotherapy for patients with a maximum of four bone metastases in addition to systemic therapy. However, since in most of the included studies on the role of prostate radiotherapy in patients with mHSPC the underlying systemic therapy was ADT alone, the significance of prostate radiotherapy in the context of modern intensified systemic therapies remains unclear, which is reflected in a weakened ‘may’ recommendation (grade of recommendation 0).

Whether radical prostatectomy can produce a similar survival benefit as radiotherapy has not yet been conclusively determined. So far, mainly registry data are available to address this question. Larger prospective phase III studies have either been discontinued or are ongoing, owing to a slow recruitment process. Thus, the S3-level clinical practice guideline recommends to only perform radical prostatectomy as part of a multimodal management approach after discussion in an interdisciplinary tumor board (2).

Metastasis-directed therapy

Metastasis-directed therapy is designed for patients with few metastatic lesions and treats ideally all lesions visualized in imaging studies with radiotherapeutic or surgical interventions in a targeted manner. To date, only limited data are available from small randomized phase II studies. In the STOMP trial, metastasis-directed therapy resulted in an increase in 5-year ADT-free survival by 26% in comparison to surveillance alone (p = 0.06) (30). In the ORIOLE study, the targeted use of stereotactic ablative radiotherapy reduced the risk of progression at six months from 61% to 19% (p = 0.005) (31). A survival benefit has not be demonstrated yet. Despite these very low case numbers, metastasis-directed therapy is already widely used in routine clinical practice. Education on the experimental nature of this treatment approach is urgently needed.

Decision criteria for treatment selection

With so many treatment options for mHSPC now available, making treatment decisions can be challenging for both clinicians and patients. Key decision criteria include the patient‘s preference, comorbidities and physical fitness for systemic therapy, as well as the potential aggressiveness of the disease. Synchronous metastatic disease with visceral involvement and high tumor burden indicates an unfavorable disease course. By contrast, patients with metachronous metastatic disease and low tumor burden have a significantly better prognosis.

So far, no direct comparison between hormonal chemotherapy and intensified hormone therapy with a new hormonal agent has become available. Only during one phase of the STAMPEDE trial, patients were randomized to either the docetaxel arm or the abiraterone arm. Here, it appeared that the two treatment options were equal in terms of the achieved overall survival (32); however, this analysis was not pre-specified. Similarly, several meta-analyses showed no significant difference between hormonal chemotherapy and the various intensified hormone therapies with abiraterone, apalutamide or enzalutamide (33, 34). Subgroup analyses can provide some guidance for decision making. For example, docetaxel combinations in patients with low tumor burden are less convincing than NHAs. By contrast, AR inhibitors appear to be less effective in patients with visceral metastases. Based on the study results and subgroup analyses, the authors have developed a graphical decision aid for patients with mHSPC (Figure).

Figure

Treatment algorithm for metastatic, hormone-sensitive prostate cancer

Precision oncology as a future decision aid

The clinical criteria for assessing the aggressiveness of the disease only allow limited conclusions as to the actual biology underlying each individual tumor. However, tumor biology is likely to have significant influence on how quickly cancer cells can develop mechanisms which help them to evade the various treatment approaches by becoming resistant. Examples include changes in specific high-risk genes which are associated with reduced effectiveness of radiotherapy, NHAs and chemotherapy with docetaxel (31, 35, 36). In case the AR signaling pathway loses its central function over the course of treatment, activation of alternative signaling pathways can result in the development of very aggressive disease courses. In this situation, early loss of effectiveness of all standard therapies used in the hormone-sensitive setting should be expected (37, 38). By contrast, intracellular processes resulting in a stabilization of the AR signaling pathway are associated with an increased sensitivity to NHAs (39).

Outlook

The management of mHSPC has undergone fundamental changes in recent years and further new treatment approaches are currently being explored in randomized phase III trials (eTable). For example, the option of starting an immunotherapy with checkpoint inhibitors or PSMA ligand therapy early in the disease course is being evaluated. Several vaccination strategies, among others, are in early clinical development, frequently in combination with checkpoint inhibitors to increase efficacy (for example NCT03532217). Given these many new therapeutic strategies, further changes in the first-line therapy of mHSPC can be expected.

eTable

Selection of currently active phase III studies on patients with metastatic hormone-sensitive prostate cancer

Conflict of interest statement
Prof. Merseburger received funds in his function as an advisor and speaker at symposia as well as for study-related activities from Astellas, Bayer, Janssen, Ipsen, Roche, Recordati, Takeda, and MedUpdate.

Prof. von Amsberg received consulting fees from Roche, BMS, Astellas, Janssen, MSD, Ipsen, Pfizer, AstraZeneca, and Merck. She received fees for presentations, ad boards and consulting from Roche, BMS, Astellas, Janssen, MSD, Ipsen, Pfizer, AstraZeneca, Merck, Sanofi, and Bayer. She received travel expense support from Roche, BMS, Janssen, Ipsen, Pfizer, Merck, Bayer, and Astellas. She is receiving fees for being an advisory board member from Roche, BMS, Astellas, Janssen, MSD, Ipsen, Pfizer, AstraZeneca, Merck, and Bayer. She received funds for industry-sponsored clinical trials in the field of urogenital tumors from Astellas, MSD, Lilly, Pfizer, AstraZeneca, Merck, Sanofi, and Avencell.

PD Böhmer is a board member of the S3 guideline committee and deputy speaker and board member of the Working Group Radiooncology (ARO) of the German Cancer Society.

Prof. Krause received financial support from AAA/Novartis, Bayer, Janssen, and PSI CRO. He received consulting fees from AAA/Novartis, PSI CRO, Janssen, and Terumo. He received lecture fees, reimbursement of travel expenses and payment of congress fees from AAA/Novartis. He is member of the advisory board at ITM solucin GmbH. Furthermore, he was the President of the German Society of Nuclear Medicine (DGN. Deutschen Gesellschaft für Nuklearmedizin) from 2016 to 2021.

PD Perner and Prof. Krabbe declare no conflict of interest.

Manuscript received on 8 April 2022, revised version accepted on 26 July 2022.

Translated from the original German by Ralf Thoene, MD.

Corresponding author:
Prof. Dr. med. Axel S. Merseburger
Klinik für Urologie, Universitätsklinikum Schleswig-Holstein
Campus Lübeck
Ratzeburger Allee 160, 23538 Lübeck, Germany

Cite this as:
Merseburger AS, Krabbe LM, Krause BJ, Böhmer D, Perner S, von Amsberg G: The treatment of metastatic, hormone-sensitive prostatic carcinoma. Dtsch Arztebl Int 2022; 119: 622–32. DOI: 10.3238/arztebl.m2022.0294

►Supplementary material

eTable, eCase report:
www.aerzteblatt-international.de/m2022.0294

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