Androgen Receptor Gene Pathway in Oligometastatic Prostate Cancer: History
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Christos Mikropoulos
,
Stergios Boussios
,

Stereotactic ablative body radiotherapy (SABR) is currently used as a salvage intervention for men with oligometastatic prostate cancer (PC), and increasingly so since the results of the Stereotactic Ablative Body Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) trial reported a significant improvement in overall survival with SABR. The addition of androgen deprivation therapy (ADT) to localised prostate radiotherapy improves survival as it sensitises PC to radiotherapy-induced cell death. The importance of the androgen receptor (AR) gene pathway in the development of resistance to radiotherapy is well established.

  • prostate cancer
  • oligometastases
  • stereotactic ablative body radiotherapy

1. Introduction

Prostate cancer (PC) is the second most commonly diagnosed cancer in males worldwide and the fifth most common cause of cancer-related death in men [1]. Despite diagnostic and therapeutic achievements, very few biomarkers have been implemented in routine clinical practice to date [2]. Angiogenesis plays a major role in the development and spread of PC [3]. Similar to other cancers, epigenetic and somatic or germline genetic modifications lead to a higher risk of PC and its progression [4]. At diagnosis, 80–90% of PCs are dependent on androgens. Androgen deprivation therapy (ADT), which reduces serum androgens and inhibits androgen receptors (ARs), is the cornerstone of PC treatment [5]. It is also one of the first examples of targeted anti-cancer therapy. Patients with high-risk non-metastatic PC who receive ADT with combination therapy (abiraterone and/or enzalutamide) have significantly better metastases-free survival and overall survival than those who receive ADT alone [6]. ARs are expressed in primary PC and metastases and regulate cell proliferation, apoptosis, migration, invasion and differentiation [7][8]. Several luteinising hormone-releasing hormone (LHRH) analogues are available that can effectively halt androgen production by the testicles and render men castrated within 2–4 weeks. The most commonly used agents are goserelin, leuprolide and triptorelin. A new addition to the armamentarium is LHRH antagonists, such as degarelix. LHRH antagonists achieve castration more quickly (within approximately 3 days) and avoid the initial surge in gonadotrophin or androgen levels seen with LHRH analogues, which can lead to the tumour flare effect. Despite being a very effective treatment initially, patients with metastatic PC become resistant to ADT in a median time of 12–18 months after the initiation of treatment [9].
Localised PC may be managed by radical prostatectomy, external beam radiotherapy or brachytherapy, or monitored within an active surveillance pathway (for patients with low-risk disease) or a watchful waiting pathway (for patients not suitable for potentially curative treatment options). Treatment depends on patient choice, fitness and the stage and grade of the PC. External beam radiotherapy is commonly used in patients with intermediate- or high-risk PC and can achieve high cure rates; the CHHIP trial reported a 90% failure-free survival at 5 years [10]. Despite this, many men relapse and require further treatment. Unfortunately, 30–50% of patients undergoing radical radiotherapy for localised prostate cancer will experience biochemical recurrence within 10 years [11]. Metastatic PC remains incurable despite much research and many therapeutic advances.
The oligometastatic paradigm was initially defined by Hellman and Weichselbaum in 1995. Oligometastatic disease is an intermediate stage of cancer between localised and systemic disease when a salvage approach is feasible. The likelihood of the oligometastatic state is dependent upon tumour biology. Tumours detected early in their progression may have metastases limited in number and anatomic site. Historically, oligometastatic disease has been treated with systemic therapies aimed at disease control. There is increasing evidence and interest in managing oligometastatic disease with ablative treatments [12]. The analysis of relapse patterns after the radical treatment of localised prostate cancer has indicated that most patients relapse with three or fewer metastases [13][14].
There is a significant discrepancy in the definition of oligometastases. The ESTRO-ASTRO consensus is that of 1–5 metastatic lesions which can all be safely treated. Oligo-recurrence is often used interchangeably with metachronous oligometastatic disease and can be defined as oligometastatic recurrence at least 3 months after the initial diagnosis. Oligoprogression is used to describe progression in a limited number of metastases, whilst the majority of metastases are stable or responding [15].
It is highly likely that an increasing number of patients will be diagnosed with oligometastatic PC due to advances in imaging, particularly with the increasing use of prostate specific membrane antigen (PSMA) positron emission tomography (PET) scans, which can detect disease recurrence at an earlier stage with lower prostate specific antigen (PSA) levels than conventional imaging (computed tomography and bone scintigraphy). The PSMA protein is a type 2 transmembrane protein expressed in large quantities on virtually all PC cells; its expression increases with the aggressiveness of the PC. PSMA is not expressed in high levels in normal prostate tissue. PSMA PET scans include a molecule linked to a radioisotope (often gallium-68) that specifically binds to the PSMA protein. PSMA is also a target for the treatment of PC [16][17][18].

2. Stereotactic Ablative Body Radiotherapy

Stereotactic ablative body radiotherapy (SABR) enables a very high dose of external beam radiotherapy to be delivered safely and with precision to a target volume. It is a non-invasive outpatient treatment. The doses delivered are biologically similar to those with brachytherapy and have equivalent or lower side effects [19]. SABR is a treatment option for patients who present with up to three or five sites of oligometastatic disease. These sites can include bone, lymph node and other soft tissue metastases. Treatment is usually delivered in three to five fractions on alternate days with a conventional linear accelerator, a magnetic resonance linear accelerator or a CyberKnife machine. A ‘day zero’ appointment is often scheduled where the patient attends the radiotherapy department for a preliminary run-through on the treatment machine to ensure that the safe delivery of treatment is going to be technically possible.
To date, multiple phase II randomised controlled trials have demonstrated the safety and efficacy of treating oligometastases with SABR. In the Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) international randomised phase II trial, a median survival benefit of 22 months was noted for patients with 1–5 oligometastases treated with SABR compared to the palliative standard of care therapy across different tumour sites. This translated to an absolute survival benefit of 24.6% at 5 years. Importantly, SABR did not result in a detriment to the patients’ quality of life. Of the 99 patients randomised within this trial, 16 (16%) had PC. The trial did not report on the use of ADT with SABR in the patients within the intervention arm [20][21]. A meta-analysis of 21 trials comprising 943 patients and 1290 oligometastases found that SABR was safe and well tolerated in the oligometastatic setting with good rates of local control. A subgroup analysis was conducted for PC oligometastases, which had an excellent 1-year local control rate of 97.9% [22].
The Observation vs. SABR for Oligometastatic PC (ORIOLE) phase II trial randomised 54 men with hormone-sensitive PC and 1–3 oligometastases to receive SABR or observation. Patients did not receive ADT in either arm until evidence of disease progression. This trial reported an improvement in progression-free survival (PFS) with SABR with no additional grade three toxicities compared to the observation group. With a median follow up of 18.8 months, median PFS was not met for patients treated with SABR compared to 5.8 months for patients undergoing observation (p value = 0.002). The local control of oligometastases treated with SABR was excellent (98.9% at 6 months) [23].
In the Surveillance or Metastasis-directed Therapy for Oligometastatic Prostate Cancer Recurrence (STOMP) trial, asymptomatic patients with up to three oligometastatic sites of recurrent prostate cancer were randomised to either metastasis-directed therapy (MDT) of all lesions or surveillance. Of the 31 patients randomised to receive MDT, 25 patients (81%) received SABR, and the remaining six patients (19%) underwent surgery. Patients did not receive ADT with MDT. No grade 2 or higher toxicity was observed in the MDT arm. The primary end point was ADT-free survival. The 5-year ADT-free survival was 8% in the surveillance group and 34% in the MDT group [24][25].
SABR-COMET-3 and SABR-COMET-5 are phase III randomised controlled trials that are currently recruiting to further investigate the overall survival benefit of SABR for up to three and 4–10 oligometastases, respectively. The outcomes measured include overall survival, progression-free survival, toxicity, quality of life and an economic evaluation.
Despite very promising results from the SABR-COMET, ORIOLE and STOMP trials, there is space to further improve the outcome of patients with hormone-sensitive oligometastatic PC (Table 1). Following the paradigm of multiple large randomised controlled trials demonstrating a survival benefit with the addition of ADT to radiotherapy in localised PC, an obvious and relatively simple way to improve patient outcomes would be to combine ADT with SABR [26][27][28].
Table 1. Radiotherapy for oligometastatic disease; summary of key trial findings.
Trial, Author (Year of Publication) Summary and Main Findings Reference
SABR-COMET, Palma, D.A.; et al. (2019) Patients with 1–5 oligometastases were randomised to receive SABR or the palliative standard of care. [20]
Median survival benefit of 22 months and absolute survival benefit of 24.6% at 5 years with SABR.
ORIOLE. Phillips, R.; et al. (2020) Patients with PC and 1–3 oligometastases were randomised to receive SABR or observation. [23]
Improvement in PFS with SABR, with a median follow up of 18.8 months PFS not met in SABR arm versus 5.8 months in the observation arm.
Local control of oligometastases treated with SABR was 98.9% at 6 months.
STOMP, Ost, P.; et al. (2018) Patients with PC and 1–3 oligometastases were randomised to MDT or surveillance. [25]
5-year ADT-free survival was 34% in MDT arm and 8% in the surveillance arm.
Abbreviations: ADT—androgen deprivation therapy; MDT—metastasis-directed therapy; PC—prostate cancer; PFS—progression-free survival; SABR—stereotactic ablative body radiotherapy.

3. Androgen Deprivation Therapy in Localised Prostate Radiotherapy

Over 20 randomised controlled trials have demonstrated the importance of the addition of ADT to radiotherapy in PC [29]. It is generally recommended that patients with intermediate-risk PC receive 6 months of ADT and patients with high-risk PC receive a longer course of ADT (2–3 years); in addition, ADT should start 2 months before radical radiotherapy.
In 1997, Bolla et al. randomised patients with locally advanced prostate cancer to either radical prostate radiotherapy with 3 years of a LHRHa starting on the first day of radiotherapy or radiotherapy alone. Patients who received a LHRHa experienced better local control and an improved overall survival. D’Amico et al. also demonstrated a significant overall survival benefit with the addition of 6 months of ADT to radical radiotherapy in patients with intermediate- or high-risk prostate cancer. ADT commenced 2 months prior to radiotherapy, concurrently and adjuvantly [26][27][28].
The addition of ADT to radiotherapy has demonstrated a clear benefit in locally advanced prostate cancer. Several trials were subsequently conducted to investigate and determine the optimal duration of ADT with radiotherapy for PC. The TROG 96.01 trial investigated whether 3 months or 6 months of neoadjuvant ADT decreased clinical progression and mortality after radiotherapy for locally advanced prostate cancer. ADT began 2 months before RT in the 3-month duration ADT group and 5 months before radiotherapy in the 6-month ADT group. Six months of neoadjuvant ADT significantly decreased distant progression and all-cause mortality compared with radiotherapy alone. Three months of neoadjuvant ADT did not demonstrate the same benefit [30]. The EORTC trial published in 2009 randomised men with locally advanced prostate cancer to receive either 6 months of ADT or 3 years of ADT with radical radiotherapy. ADT consisted of LHRHa, which was commenced on the first day of radiotherapy. At 5 years, the overall mortality was 3.8% higher in the short-term ADT arm than the long-term ADT arm of the trial; however, this did not demonstrate statistical significance [31]. The RTOG 9202 trial compared 4 months of ADT with 2 years of ADT in locally advanced prostate cancer. ADT commenced 2 months before the start of radiotherapy. Two years of ADT resulted in a significant improvement in disease-free survival. The benefit of the longer course of ADT was greater in patients with a higher Gleason score (8 to 10), and a significant improvement in overall survival was also observed in this group of patients [32].
The timing of ADT in relation to radiotherapy is crucial in optimising the additional benefit. Simply increasing the duration of ADT in unselected patients does not necessarily improve outcomes [33]. As ADT is associated with adverse effects on the cardiovascular system, bone health and overall quality of life, it is imperative to treat only the patients who will benefit from ADT at the correct time and for the shortest duration indicated [33][34].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23094786

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