Luteinizing hormone-releasing hormone receptor agonists and antagonists in prostate cancer: effects on long-term survival and combined therapy with next-generation hormonal agents

Abstract

Prostate cancer is a leading cause of cancer-related death in men worldwide. Luteinizing hormone-releasing hormone receptor (LHRH-R) agonists and antagonists are known to achieve castration-level testosterone suppression; however, long-term data comparing the survival benefits of these therapies are insufficient to inform treatment decisions. Furthermore, the advent of next-generation hormonal agents (NHAs), such as abiraterone and enzalutamide, have shifted the paradigm of managing prostate cancer. Although LHRH-R agonists and antagonists remain the cornerstone treatment across various stages of prostate cancer, they are increasingly administered with NHAs, because the combination treatment confers a survival advantage. Nevertheless, the differences in efficacy and safety profiles among various combinations of LHRH-R agonists and antagonists and NHAs remain unclear. Hence, this narrative review is aimed at providing a comprehensive overview of the long-term outcomes of various LHRH-R agonists and antagonists. Key data from major clinical studies are summarized, categorized by disease stage. LHRH-R agonists and antagonists, particularly goserelin, have demonstrated long-term survival benefits in patients with localized and locally advanced prostate cancer. The clinical outcomes of different LHRH-R agonists and antagonists in combination with NHAs have also been evaluated. Among the various combinations, goserelin plus abiraterone appears to have a manageable safety profile with relatively low rates of hot flushes and fatigue. Overall, long-term survival data and safety profiles should be considered in selecting optimal combination therapies for prostate cancer treatment.

Introduction

Prostate cancer (PC) is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide¹. In 2022, an estimated 1,466,718 new cases and 396,773 deaths were attributed to this disease². The understanding of PC as androgen-dependent tumors has provided the rationale for achieving and maintaining serum testosterone concentrations at castration levels in patients with PC³.

The first report of medical castration dates to 1941, when Huggins et al.⁴ demonstrated that estrogen injection or castration inhibits PC progression. Subsequently, in 1945, Huggins and Scott⁵ discovered that the adrenal gland is also an important source of testosterone, thus stimulating interest in medical castration of adrenal androgens. Another milestone occurred when Schally et al.⁶ elucidated the structure and physiological functions of luteinizing hormone-releasing hormone (LHRH) and described a method to synthesize it. This seminal study sparked great interest in LHRH analogues, and subsequently led to preclinical demonstration of testosterone suppression after an initial surge and demonstration of benefits in PC^7,8. Subsequently, several LHRH analogues, known as luteinizing hormone-releasing hormone-receptor (LHRH-R) agonists, were developed and approved for clinical use⁹. The timeline of events leading to the development of LHRH-R agonists is presented in Figure 1. LHRH-R antagonists, which were initially developed for contraceptive purposes, have also been investigated as treatments for PC and demonstrated to be as effective as LHRH-R agonists¹⁰.

Figure 1.

Timeline of events in the development of LHRH-R agonists. LHRH-R, luteinizing hormone-releasing hormone receptor.

To date, androgen deprivation therapy (ADT) modalities include orchiectomy, LHRH-R agonists, LHRH-R antagonists, estrogens, and anti-androgens, which suppress the secretion of testicular androgens through different routes. LHRH-R agonists and antagonists, the primary pharmacological castration options in ADT, effectively lower androgen levels and thereby inhibit PC cell growth¹¹. Mounting evidence indicates their efficacy and safety in clinical trials; however, given the complexity of the data, determining the optimal treatments in different treatment settings is difficult. Whereas previous meta-analyses and comparative reviews suggest that different LHRH-R agonists and antagonists yield comparable castration effects^3,12, limited reports have compared their effects on long-term survival, the primary efficacy endpoint.

Although most patients respond to initial treatment with ADT, castration-resistant PC (CRPC) eventually develops. In CRPC, intracellular androgen levels are elevated, and the androgen receptor (AR) is overexpressed. To address these issues, novel compounds such as next-generation hormonal agents (NHAs) have been developed to block AR signaling¹³. Combining LHRH-R agents with NHAs improves overall survival benefits beyond those of LHRH-R agents alone in patients with metastatic, hormone-sensitive PC and castration-resistant PC^14–17. Nevertheless, limited evidence is available comparing the efficacy and safety profiles of various LHRH-R agonists and antagonists combined with NHAs.

This narrative review is aimed at exploring and comparing the long-term treatment outcomes of various LHRH-R agonists and antagonists, and reviewing the efficacy of those agents in combination with NHAs; the safety profiles of various treatments are also discussed. We hope to provide valuable insights to inform the use of LHRH-R agonists/antagonists in various clinical settings.

Mechanisms of action of LHRH-R agonists, antagonists, and NHAs

The mechanisms of action of LHRH-R agonists and antagonists are depicted in Figure 2. LHRH produced within the hypothalamus binds the LHRH-Rs and stimulates the anterior pituitary gland to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH)^10,11. LH in turn binds the LH receptors in the testes, and induces the production and secretion of testosterone. Testosterone, together with other androgen precursors produced in the adrenal gland, is converted by 5α-reductase to 5α-dihydrotestosterone (DHT) in prostate cells; subsequently, DHT binds the AR, thus resulting in downstream gene amplification and expression. Constitutive activation of the AR signaling plays key roles in the survival, growth, and proliferation of PC cells¹¹.

Figure 2.

Schematic diagram of mechanisms of action for LHRH-R agonists, LHRH-R antagonists, CYP17 inhibitors, and androgen receptor antagonists: (1a) LHRH-R agonists bind the LHRH-R and elicit an initial gonadotropin surge. Prolonged stimulation of LHRH-R along the hypothalamic-pituitary-gonadal axis eventually suppresses LH and testosterone. (2a) LHRH-R antagonists block interaction of LHRH with LHRH-R by directly occupying the binding sites on LHRH-R. (1b and 2b) In prostate cancer cells, LHRH-R is activated not only by LHRH-R agonists but also by LHRH-R antagonists, thereby leading to Gαi/cAMP activation. The Gαi/cAMP pathway triggers inactivation of tyrosine kinase receptors (e.g., EGF-R and IGF-1R) and interferes with downstream molecular pathways (e.g., MAPK and PI3K/AKT cascades), thus resulting in antiproliferative, apoptotic, antimetastatic, and antiangiogenic effects in prostate cancer cells. (3) CYP17 inhibitors suppress the synthesis of testosterone targeting the CYP17A. (4) AR antagonists inhibit DHT binding to the androgen receptor, thereby preventing androgen receptor nuclear translocation and subsequently blocking AR-mediated transcription. AKT, protein kinase B; AR, androgen receptor; cAMP, cyclic adenosine monophosphate; DHT, dihydrotestosterone; ERK, extracellular signal-regulated kinase; FSH, follicle-stimulating hormone; LH, luteinizing hormone; EGF-R, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; LHRH, luteinizing hormone-releasing hormone; LHRH-R, LHRH receptor; MAPK, mitogen-activated protein kinase; p-JNK, phospho-c-Jun N-terminal kinase; PAI-1, plasminogen activator inhibitor-1; PI3K, phosphoinositide 3-kinase; uPA, urokinase plasminogen activator.

Natural LHRH is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂). LHRH-R agonists (for example, goserelin, triptorelin, leuprolide, histrelin, and buserelin) are synthetic peptides that mimic endogenous LHRH but bear modifications at the sixth and/or tenth amino acid that improve their half-life and potency¹⁸. LHRH-R agonists bind the LHRH-R and elicit an initial gonadotropin surge, which is described as a “flare-up” phenomenon that may last approximately 1 week. Concomitant therapy with an anti-androgen decreases the incidence of clinical flares, and sustained overstimulation of LHRH-R by LHRH-R agonists causes downregulation and desensitization of the receptors, thus decreasing gonadotropin production by the pituitary gland and subsequently decreasing testosterone levels¹⁹. Decreasing testosterone to castration levels can usually be achieved within 2–4 weeks of treatment²⁰. In addition, LHRH-R agonists inhibit the mitogenic activity of growth factors such as insulin-like growth factor 1 and epidermal growth factor and their downstream signaling pathways in PC cells, in another mechanism explaining their anti-proliferative and pro-apoptosis effects^21,22. In contrast, LHRH-R antagonists block interaction of LHRH with LHRH-R by directly occupying the binding sites on LHRH-R, thus decreasing LH and FSH production, and consequently testosterone levels. In this category, degarelix is a decapeptide with high affinity and selectivity toward human LHRH-R²³. The presence of substitutions at multiple sites in LHRH and accompanying structural changes are believed to be associated with the release of histamine and the occurrence of severe hypersensitivity reactions²⁴. LHRH-R antagonists induce sex hormone depletion rapidly and do not cause an initial serum testosterone flare¹⁰. Additionally, LHRH-R antagonists bind the LHRH-R in PC cells and interfere with growth factor receptor signaling pathways, thereby suppressing tumor growth and promoting apoptosis²². LHRH-Rs are also expressed in CRPC cells, where the binding to both agonists and antagonists results in anti-tumor effects mediated via the Gαi-cAMP signaling pathway²².

Although the mechanisms of action of ADT plus radiation or surgery have not been established, the antitumor efficacy of radiotherapy improves in combination treatment with ADT, which enhances the radiation effects and decreases micro-metastases; similarly, the addition of ADT to prostatectomy can also prevent micro-metastases^25–29.

LHRH-R agents effectively inhibit tumor growth in castration-sensitive PC; however, tumors inevitably become castration resistant over time. The mechanisms responsible for castration-resistant status are mediated primarily by AR signaling, although AR-independent mechanisms have also been reported³⁰. Hence, novel drugs have been developed to target the AR signaling axis in CRPC. Abiraterone acetate is a sterol ester that selectively inhibits CYP17 (a combination of 17α-hydrolase and 17,20-lyase inhibition)³¹. By blocking CYP17, a key enzyme in the androgen synthesis pathway, abiraterone acetate significantly decreases intracellular testosterone levels by suppressing its synthesis in the adrenal glands and testes, and within cancer cells³². The metabolite abiraterone also has inhibitory activity against CYP17 and enzymes involved in DHT synthesis, and additionally has competitive AR antagonism functions³³. Novel non-steroidal anti-androgens, such as the benzamide enzalutamide, exhibit greater affinity toward the AR than first-generation anti-androgens^34,35, which act as partial agonists but still allow AR transfer to the nucleus. The novel non-steroidal anti-androgens block AR transfer and therefore suppress any possible agonist-like activity. Inhibition of AR signaling results in blockade of downstream gene expression, and inhibition of PC cell survival and growth. The combination of LHRH-R agents and anti-androgens^36,37, also known as maximal androgen blockade, not only inhibits the action of circulating androgens but also decreases intracellular testosterone levels by blocking androgen synthesis and nuclear transfer of ARs. Combining LHRH-R agents with anti-androgens improves anticancer activity toward castration-resistant PC and is currently an important treatment strategy for the disease. The properties of the various drug classes discussed herein are presented in Table S1.

LHRH-R agonists and antagonists provide long-term benefits across various stages of PC

The long-term survival outcomes of patients with PC receiving treatment with various LHRH-R agonists and antagonists in clinical trials are summarized in Figure 3 and Table S2.

Figure 3.

Follow-up durations and overall survival estimates for LHRH-R agonist and antagonist treatment of prostate cancer. Lengths of bars represent the study follow-up duration for the treatment groups, and numbers in circles represent the estimated survival rate. For example, Zapatero et al.³⁸ reported a 5-year survival estimate of 95% with 64 months of study follow-up in the long-term goserelin + radiotherapy group. Some studies did not report survival estimates; therefore, some bars in the figure do not have survival rate percentages. Note: 13 of 46 patients in Messing et al.³⁹ underwent bilateral orchiectomy, and the others received goserelin. LHRH-R, luteinizing hormone-releasing hormone receptor; PSA, prostate-specific antigen; RT, radiotherapy.

The durations of follow-up varied widely across studies, from 12 months^20,40–42 to 143 months^39,43. Generally, studies involving goserelin^{38,39,43–61} had longer follow-up durations, and were more likely to report long-term survival estimates than studies involving leuprolide, triptorelin, degarelix, or unspecified LHRH-R agonists and antagonists, particularly in the settings of locally advanced and metastatic PC (Figure 3)^{38,39,62–67}. Studies of goserelin had a median follow-up duration as high as 143 months^39,43, whereas the corresponding durations were limited to 101 months for triptorelin and 91 months for leuprolide^68,69. In contrast, most studies with short-term follow-up (1–3 years)^{20,40–42,70,71} did not provide long-term survival estimates. Several studies with intermediate-term follow-up (4–5 years)^47,58,61,66 reported long-term survival estimates beyond the study follow-up duration. Given the challenges associated with estimating survival from extrapolation of survival data⁷², particularly given that > 70% of death events were not observed at the end of a study⁷³, reporting of long-term follow-up data is expected to be particularly informative for patients with PC, in whom intermediate-term survival rates typically exceed 70%. In this regard, studies with long-term follow-up durations (beyond 5 years) should provide valuable insights into the effects of LHRH-R agents on patient survival, to inform treatment decisions regarding various agents.

LHRH-R agents are used in various settings for PC treatment; therefore, studies on LHRH-R agonists/antagonists are discussed herein in the context of localized^{38,44–47,62}, locally advanced^{39,43,48–58,63–66,68,69,74,75}, or metastatic^{40,59–61,67,70,71,76–79} disease stages.

LHRH-R agents in localized PC

For localized PC, the combination of LHRH-R agonists and non-steroidal anti-androgens has been extensively studied in patients undergoing radiotherapy^{38,44–47,62}. As shown in Figure 3, the DART01/05 GICOR study enrolled patients with localized PC using a specific LHRH-R agonist (goserelin) and reported 5-year survival estimates. Other studies of LHRH-R agonists in this setting either did not specify the type of LHRH-R used or reported pooled data from several LHRH-R agonists. Typically, LHRH-R agonists were administered as short-term (4 or 6 months) ADT or prolonged (36 weeks or 28 months) ADT before radiotherapy. For patients treated with radiotherapy plus short-term ADT, the estimated 5-, 8-, 10-, and 18-year survival rates were 86%–88%, 74%, 62%–67%, and 23%, respectively^{38,44–47,62}. In patients treated with radiotherapy and prolonged ADT, the estimated 5-year and 10-year survival rates were 95% and 67%, respectively.

Inconsistent overall survival results were reported in studies comparing long-term vs. short-term ADT (with LHRH-R agonists/antagonists) in patients with PC undergoing radiotherapy. The results should be interpreted in view of differences in study designs and patient populations; in particular, radiation dosage, ADT agent, and category of disease risk might have influenced the overall survival outcomes with long-term ADT³⁸. The DART01/05 GICOR study demonstrated that radiotherapy plus prolonged (28 months) goserelin treatment yielded a higher 5-year survival rate than radiotherapy plus short-term (4 months) goserelin treatment (95% vs. 86%, P = 0.009)³⁸. In contrast, the RTOG 9910 study indicated that prolonged-duration (36 weeks) LHRH-R agonist treatment did not lead to higher 10-year survival rates (67% vs. 66%) or 10-year disease-specific survival (96% vs. 95%) than short duration (16 weeks) LHRH-R agonist treatment, after 113 months of follow-up⁶². Of note, apart from the various ADT agents used, the radiation dosage in the DART01/05 GICOR study (range, 76–82 Gy) was higher than that in the RTOG 9910 study (70.2 Gy). Moreover, more patients in the DART01/05 GICOR study than the RTOG 9910 study had high-risk disease (90% vs. 15%); therefore, the benefits of long-term ADT plus radiotherapy in overall survival might be more evident in patients with high-risk PC than in those with low-risk disease³⁸. Existing overall survival evidence favors the use of goserelin as either short-term or long-term ADT, although evidence for other particular ADT agents is limited.

LHRH-R agents in locally advanced PC

Combining ADT with radiotherapy is currently the standard of care for patients with intermediate- and high-risk localized PC⁸⁰. Here, we summarize the survival outcomes of ADT in this patient population across various treatment settings, including ADT concomitant with radiotherapy, ADT before or after radical prostatectomy, and ADT at biochemical recurrence after radical treatment.

ADT concomitant with radiotherapy

In studies reporting concomitant use of ADT (goserelin^{43,48,51,52,54–56}, leuprolide^69,74, triptorelin⁷⁵, or unspecified^63,65) with radiotherapy, the initiation of ADT ranged from 5 months before radiotherapy to the first day of irradiation, with durations ranging from 3 months to disease progression. The TROG 96.01 trial, exploring neoadjuvant ADT (goserelin) given concurrently with radiotherapy, showed that 6-month neoadjuvant treatment resulted in a significantly lower 10-year all-cause mortality rate (29.2% vs. 42.5%) and PC-specific mortality rate (11.4% vs. 22.0%) than radiotherapy alone; however, 3-month neoadjuvant ADT had no effects on the all-cause mortality rate and PC-specific mortality rate⁵¹. Another study, RTOG 8610, revealed that the addition of 4 months of goserelin (2 months before and concurrent with radiotherapy) appeared to confer overall survival benefits beyond those of radiotherapy alone (10-year overall survival: 42.6% vs. 33.8%)⁴³.

The EORTC 22863 study showed that initiation of goserelin on the first day of irradiation and continuing for 3 years increased 10-year overall survival and disease-free survival beyond that with radiotherapy alone⁵⁴. Therefore, ADT concomitant with radiotherapy is a preferred treatment option for locally advanced PC. Regarding the optimal duration of ADT, a phase 3 study by Bolla et al.⁷⁵ showed that long-term (36 months) ADT (triptorelin) led to a higher 5-year overall survival rate, with a follow-up of 6.4 years, than short-term (6 months) ADT (triptorelin). Meanwhile, the DART01/05 GICO study also reported that 2 years of ADT (goserelin) combined with radiotherapy increased 5-year overall survival and biochemical control beyond those with short-term ADT combined with radiotherapy³⁸. The RTOG 92-02 study showed that long-term goserelin treatment (24 months) plus radiotherapy achieved more favorable disease-free survival, disease-specific survival, and biochemical recurrence but did not result in superior survival to short-term ADT plus radiotherapy⁴⁸. Although a study by Nabid et al.⁵² in 2018 indicated no difference in survival when patients received 36 vs. 18 months of ADT (goserelin) combined with radiotherapy, the study enrolled few patients with disease stage of T3 or above. Current treatment guidelines recommend radiotherapy combined with short-term (4–6 months) ADT for unfavorable intermediate-risk PC, and endorse radiotherapy combined with long-term (2–3 years) over short-term ADT in patients with high- or very-high-risk disease⁸⁰.

The survival benefits associated with a combination of goserelin and radiotherapy are supported by substantial research with long-term survival follow-up data demonstrating a decade-long overall survival rate ranging from 43% to 62%^43,52. Additionally, studies indicated that leuprorelin plus radiotherapy resulted in an overall survival rate of 72% after 67 months of follow-up⁷⁴, whereas triptorelin combined with radiotherapy led to a 5-year overall mortality of 19.0%, with 77 months follow-up⁷⁵.

ADT before or after radical prostatectomy

Studies investigating the effects of neoadjuvant ADT before radical prostatectomy have associated combination therapy with downstaging, a decrease in positive margins, and a diminished incidence of positive lymph node involvement. The small prospective, phase 2, single-arm SWOG 9109 study⁵⁰ showed that neoadjuvant ADT (4-month goserelin) followed by radical prostatectomy resulted in a 10-year survival rate of 68%. However, because of a lack of long-term follow-up data demonstrating survival benefits beyond those achieved with alternative treatments, neoadjuvant ADT before radical prostatectomy remains controversial.

In the SWOG S9921 study, high survival rates were observed for patients undergoing radical prostatectomy, with a 5-year survival rate of 96% after 53 months of follow-up⁵⁸ and a 10-year survival rate of 87% after 134 months of follow-up in patients treated with 2 years of ADT (goserelin)⁴⁹. All patients enrolled in the SWOG S9921 study had high risk features, such as high pathologic Gleason score, high preoperative prostate-specific antigen (PSA) level, seminal vesicle invasion, lymph node involvement, and positive margins. In the EST 3886 study, patients with nodal metastases who underwent radical prostatectomy and subsequently received immediate goserelin or bilateral orchiectomy had a median survival of 13.9 years³⁹. These results suggest that ADT after radical prostatectomy can provide long-term survival benefits in patients with high-risk disease or lymph node involvement.

ADT at biochemical recurrence after radical treatment

Several clinical trials have investigated the efficacy of combining salvage radiotherapy with ADT after radical prostatectomy. The GETUG-AFU 16 study indicated that 6 months of goserelin treatment plus salvage radiotherapy significantly increased 10-year biochemical progression, biochemical progress-free survival, and metastasis-free survival, although addition of ADT to salvage radiotherapy did not increase the 10-year overall survival rate⁵³. The NRG Oncology/RTOG 0534 SPPORT study compared the treatment of prostate bed radiotherapy (PBRT), 6 months of ADT plus PBRT, and 6 months of ADT plus PBRT and pelvic lymph node radiotherapy (PLNRT). With a median follow-up of 8.2 years, the 5-year distant metastasis incidence was lowest in the ADT plus PBRT and PLNRT group, whereas the ADT plus PBRT group had a lower distant metastasis incidence than the PBRT group⁶³. Nevertheless, no significant difference in overall survival was observed. Furthermore, the data from the RTOG 9601 study suggested that the addition of 2-year anti-androgen therapy (bicalutamide) to salvage radiotherapy in patients experiencing biochemical recurrence after RP increased both disease-specific survival and overall survival⁸¹. These randomized controlled trials support adding ADT to salvage radiotherapy⁸¹. However, because of methodological discrepancies and differences in patient populations in clinical trials, which type and duration of ADT should be added to salvage radiotherapy is not yet clear.

In summary, long-term survival benefits have been observed with ADT across various treatment settings for locally advanced PC. Existing evidence of overall survival benefits was most robust for goserelin across various settings, given the available estimated 10-year survival rates^{43,48,52,54,55}. Because overall survival is the “gold standard” endpoint for assessing efficacy in cancer treatment trials, therapeutic agents with long-term survival data available, such as goserelin, may warrant prioritized consideration in treatment decisions.

LHRH-R agents in metastatic PC

An ADT-containing regimen is the recommended first-line therapy for advanced/metastatic PC. Notable findings have been reported regarding the efficacy of LHRH-R agonists in metastatic PC, including goserelin^59–61, leuprolide⁷⁰, triptorelin⁷¹, histrelin^76–79, and buserelin⁴⁰, although long-term follow-up is lacking. In EORTC 30853, goserelin plus flutamide resulted in a median survival of 34 months in patients with bone metastases⁶⁰. After 24 months of treatment with leuprorelin, the overall survival rate was 78% in patients with stage D1 and D2 PC⁷⁰. For triptorelin, the median survival was 37.5 months in patients with previously untreated locally advanced or metastatic PC, after a follow-up duration of 38.8 months⁷¹.

With the advancement of NHAs, LHRH-R agents combined with NHAs have emerged as viable treatment options for metastatic PC. Unfortunately, no studies have shown the comparative efficacy and safety among various LHRH-R agents in the combination treatment.

LHRH-R agents have comparable safety profiles

Limited data are available on the adverse events associated with treatment with single-agent LHRH-R agonists or antagonists in patients with localized PC, because available studies have focused primarily on safety profiles during radiotherapy plus ADT treatment^38,44,47,62. The most common adverse events across LHRH-R agonists include hot flushes, skeletal pain, headache, constipation, fatigue, sexual dysfunction, general pain, testicular atrophy, joint disorder, osteoporosis, and metabolic alterations^3,12. Many of these common events may be attributable to decreased testosterone levels. The decline in luteinizing hormone and follicle-stimulating hormone caused by LHRH-R agonists during ADT treatment can lead to release of norepinephrine, thus contributing to dysregulation of peripheral vasodilatation and the occurrence of hot flushes⁸². Hot flushes and rash have been reported in 55% and 3% of patients, respectively, during 8 weeks of ADT before radiotherapy in patients with localized PC⁴⁵. ADT treatment has been associated with an elevated rate of non-metastatic bone fractures, probably because of osteoporosis¹². Increased risk of cardiovascular events has been reported after treatment with LHRH-R agonists and possibly antagonists; however, the evidence is mixed^12,83. Psychological complaints and anemia are unlikely to be the reasons for increased fatigue levels with ADT⁸⁴. Sleep disturbances associated with ADT-associated hormonal alterations can also contribute to fatigue⁸⁵. Furthermore, mitochondrial dysfunction in the central nervous system may cause fatigue during ADT⁸⁶. The safety profiles of goserelin, leuprorelin, and triptorelin are generally comparable¹². Goserelin and degarelix also exhibit similar safety profiles, although injection site reactions are more common with degarelix⁸³.

LHRH-R agonists and antagonists in combination with NHAs

PC treated with ADT eventually becomes castration resistant⁸⁷. Consequently, several new compounds targeting the androgen axis have been developed. The use of LHRH-R agonists/antagonists with NHAs has led to improvements in clinical outcomes in patients with PC. Among the various NHAs available, abiraterone and enzalutamide have been extensively studied. However, adverse events appear to be more frequent with the addition of NHAs to LHRH-R agonists or antagonists than LHRH-R agonists or antagonists alone^17,88,89. A recent meta-analysis has shown that NHAs are associated with elevated risk of cognitive toxic effects, fatigue, and falls⁹⁰.

This section focuses on studies involving single-agent LHRH-R agonists or antagonists combined with abiraterone or enzalutamide^91–101. Studies that did not specify the LHRH-R agonists or antagonists used in combination with NHA are not included. Because only several included studies reported overall survival outcomes, the effects on PSA, testosterone, and disease progression, as well as safety results, are reviewed.

LHRH-R agents can be combined with NHAs in castration-resistant and hormone-sensitive PC

Studies examining combinations of LHRH-R agonists and antagonists with abiraterone or enzalutamide are summarized in Table 1^91–101, including neoadjuvant^91–97, salvage^98,99, and advanced^100,101 treatment stages.

Table 1.

Efficacy of LHRH agonists and antagonists in combination with next-generation hormonal agents in prostate cancer^*

Author year; study phase (type of study)	Patient population	Race	Treatment duration	Regimen	N	Follow-up duration	Testosterone	PSA	Progression outcome
Neoadjuvant
Cho 201591; phase 2 (single arm)	Intermediate-risk disease (GS of 7, or PSA 10–20) or high-risk disease (T3/4, GS 8–10 or PSA > 20)	NR	24 weeks (12 weeks of neoadjuvant followed by concurrent phase with radiation therapy)	Goserelin or leuprolide + abiraterone + RT	22	21 months	Testosterone decline: 99.9%	Median pre-radiation PSA at 12 weeks: 0.05 ng/mL. All 21 men who complied with at least 3 months of abiraterone had a pre-radiation PSA nadir: ≤ 0.3 ng/mL. Post radiation PSA undetectable in 19/22 patients and: all patients who completed the neoadjuvant and concurrent portions of the study (n = 16).	21/22 patients had not experienced biochemical relapse
Shee 202292; phase 2 (single arm)	High-risk localized or regional PC, having ≥ 2 of the following criteria: cT3a/b, PSA ≥ 20 ng/mL, GS 8–10, ≥ 33% core involvement on prostate biopsy; or ≥ 1 cm pelvic lymph node(s)	White: 54.5%; Black: 18.2%; Asian: 9.1%; unknown: 18.2%	24 months before RT	Leuprolide + enzalutamide	11	35.5 months	Median time to testosterone < 50 ng/dL from initiation of ADT: 1.73 months; median nadir testosterone: 18 ng/dL	Achieved PSA-CR (PSA nadir ≤ 0.3 ng/mL) at 120 days of ADT: 90.9%. Median time to PSA-CR was: 4.20 months, and median nadir PSA was: 0.015 ng/mL.	Biochemical recurrence: 0% at 24 months and 11% at 36 months
Bastos 202293; phase 2 (randomized trial)	High-risk localized PC, GS ≥ 8 and/or cT3N0-1 and/or PSA ≥ 20 ng/mL	NR	3 months neoadjuvant before RP	Goserelin + abiraterone + RP	31	2.6 years	Testosterone recovery: 84%	NR	Biochemical relapse: 32% pCR or MRD: 7%; complete PSMA response: 23%.
Karzai 201994; phase 2 (single arm)	Newly diagnosed, high-risk PC	NR	6 months neoadjuvant before RP	Goserelin + enzalutamide + RP	33	NR	NR	Median on-study PSA was: 9.58 ng/dL. Median PSA after 6 months of goserelin + enzalutamide was: < 0.02 (0.02–0.35 ng/mL).	NR
Efstathiou 201995; phase 2 (randomized trial)	PC without metastasis, ≥ T1c with GS 8–10 or ≥ T2b with GS of 7 and PSA ng/mL	NR	3 months before RP	Leuprolide + abiraterone + RP	44	≥ 4 years	NR	PSA ≤ 0.1 ng/mL: 84%	3-year relapse-free survival: 75%; biochemical recurrence: 44%
				Leuprolide + RP	21	≥ 4 years	NR	PSA ≤ 0.1 ng/mL: 5%	3-year relapse-free survival: 71%; biochemical recurrence: 59%
McKay 201996; phase 2 (randomized trial)	GS ≥ 7 or ≥ 1 cm tumor on MRI, PSA > 20 ng/mL, or T3	White: 90%; Black or African American: 6%; other: 4%	24 weeks neoadjuvant before RP	Leuprolide + enzalutamide + abiraterone + RP	50	NR	NR	PSA ≤ 0.2 ng/mL (% patients): 96% (before RP)	pCR or MRD at RT: 30%
		White: 80%; Black or African American: 12%; Asian: 8%		Leuprolide + enzalutamide + RP	25	NR	NR	PSA ≤ 0.2 ng/mL (% patients): 100% (before RP)	pCR or MRD at RT: 16%
Taplin 201497; phase 2 (randomized trial)	Localized PC and 1 of the following: PSA > 10 ng/mL, PSA velocity > 2 ng/mL per year (in preceding 12 months), and GS ≥ 7	NR	24 weeks neoadjuvant before RP	Leuprolide (24 w) + RP	28	24 weeks	Testosterone (mean): baseline 429.4 → 12 w: 17.3 → 24 w: 5.3 ng/dL	24 w PSA (median): 0.06 ng/dL 24 w PSA ≤ 0.2 ng/mL: 82%	pCR or MRD: 48%
		NR		Leuprolide (24 w) + abiraterone (24 w) + RP	30	24 weeks	Testosterone (mean): baseline 425.1 → 12 w: 6.7 → 24 w: 15.5 ng/dL	24 w PSA (median): 0.04 ng/dL 24 w PSA ≤ 0.2 ng/mL: 93%	pCR or MRD: 62%
Salvage
Freedland 202398; phase 3 (randomized trial)	High-risk (PSA doubling time of ≤ 9 months and a PSA level of ≥ 2 ng/mL above nadir after radiation therapy or ≥ 1 ng/mL after radical prostatectomy with or without postoperative radiation therapy, testosterone ≥ 150 ng/dL, and an ECOG PS 0 or 1	White: 82.5%; Asian: 7.3%; Black: 4.5; other: 2.8%; not reported: 2.8%	36 weeks if the PSA at week 36 was < 0.2 ng/mL and restarted with increased PSA	Leuprolide + enzalutamide	355	60.7 months	NR	Free from PSA progression at 5 years: 97.4%; 90.9% of patients had treatment suspended for a median of 20.2 months.	5-year metastasis-free survival: 87.3%
		White: 83.1%; Asian: 7.3%; Black: 4.2; other: 1.4%; not reported: 3.9%		Enzalutamide	355	60.7 months	NR	Free from PSA progression at 5 years: 88.9%; 85.9% of patients had treatment suspended for a median of 11.1 months	5-year metastasis-free survival: 80.0%
		White: 84.1%; Asian: 7.3%; Black: 4.5; other: 2.5%; not reported: 1.4%		Leuprolide	358	60.7 months	NR	Free from PSA progression at 5 years:70.0%; 67.8% of patients had treatment suspended for a median of 16.8 months.	5-year metastasis-free survival: 71.4%
Autio 202199; phase 2 (randomized trial)	Had undergone an RP for localized PC; experienced biochemical recurrence; PSA doubling time at the time of trial entry: ≤ 9 months; testosterone level ≤ 150 ng/dL	White: 80%; Black or African American: 15%; unknown: 5%	8 months	Degarelix + abiraterone	41	18 months	Median time to testosterone recovery (from treatment start): 56 weeks; undetectable PSA with testosterone recovery at 18 months: 17.1%	Undetectable PSA level at 8 months: 87.8%	PSA progression: 64.4 weeks
		White: 93%; Black or African American: 7%		Degarelix	42		Median time to testosterone recovery: 52.9 weeks; undetectable PSA with testosterone recovery at 18 months: 11.9%	Undetectable PSA level at 8 months: 66.7%	PSA progression: 54.9 weeks
		White: 90%; Black or African American: 10%		Abiraterone	39		Median time to testosterone recovery: 36 weeks; undetectable PSA with testosterone recovery at 18 months: 5.1%	Undetectable PSA level at 8 months: 83.8%	PSA progression: 37.5 weeks
Advanced
Maluf 2021100; phase 2 (randomized trial)	(1) Locally advanced PC with positive lymph nodes, not candidates for radical surgery or RT and PSA ≥ 2 ng/mL; (2) high-risk biochemical recurrence: PSA ≥ 4 ng/mL and PSA doubling time < 10 months, or PSA ≥ 20 ng/mL; or (3) metastatic CSPC and PSA ≥ 2 ng/mL	NR	25 weeks (study treatment continued only at investigator discretion)	Goserelin + abiraterone	42	14 months	Testosterone level < 50 ng/dL (castration level) at week 25: 97.5%	PSA ≤ 0.2 ng/mL (% patients): 75.6% (at week 25); PSA decline ≥ 50%: 100%; PSA decline ≥ 80%: 100%	Radiographic progression (at week 25): 3.1%
George 2023101; phase 3 (randomized trial)	Advanced PC eligible for at least 1 year of continuous ADT	NR	48 weeks	Leuprolide + enzalutamide	9	NR	Sustained testosterone suppression below castration levels (< 50 ng/dL) from day 29 through 48 weeks: 90.9% (concomitant enzalutamide or docetaxel)	NR	NR
		NR		Relugolix + enzalutamide	20	NR	Sustained testosterone suppression below castration levels (< 50 ng/dL) from day 29 through 48 weeks: 95.8% (concomitant enzalutamide or docetaxel); testosterone (median): 12.71 ng/dL	NR	NR

ADT, androgen deprivation therapy; CSPC, castration-sensitive prostate cancer; GS, Gleason score; MRD, minimal residual disease; MRI, magnetic resonance imaging; NR, not reported; PC, prostate cancer; pCR, pathologic complete response; PSA, prostate-specific antigen; PSA-CR, PSA complete response; PSMA, prostate specific membrane antigen; RP, radical prostatectomy; RT, radiotherapy; w, weeks.

*A literature search was performed in core databases and supplemented by searching for studies published before February 2024.

In the neoadjuvant setting, LHRH-R agonists and antagonists plus NHAs are typically used before radiotherapy^91,92 or radical prostatectomy^93–97. In 2 clinical studies, neoadjuvant ADT plus NHA in combination with radiotherapy decreased testosterone to castration levels, PSA levels were undetectable, and biochemical recurrence rates of 5%–11% were observed during 21–35.5 months of follow-up; the regimens used in the studies were 12 weeks of goserelin or leuprolide plus abiraterone, followed by another 12 weeks of combination therapy concurrent with radiotherapy in patients with intermediate-risk or high-risk disease, as well as 24 months of leuprolide plus enzalutamide in patients with high-risk disease^91,92.

Among patients with PC who received 3-month ADT plus NHA as neoadjuvant treatment before radical prostatectomy, the biochemical relapse rate was 32% with goserelin plus abiraterone after a follow-up of 2.6 years and 44% with leuprolide plus enzalutamide after a follow-up of ≥ 4 years^93,95. Additionally, neoadjuvant therapy of 6 months ADT plus NHA before radical prostatectomy resulted in a median PSA level < 0.02 (range 0.02–0.35) ng/mL after treatment with goserelin plus enzalutamide⁹⁴; 100% of patients had PSA ≤ 0.2 ng/mL with the combination of leuprolide and enzalutamide⁹⁶; and 93% had PSA ≤ 0.2 ng/mL with leuprolide plus abiraterone⁹⁷.

Among studies involving patients with biochemical recurrence after radical prostatectomy^98,99, combination treatment with LHRH-R agonists/antagonists plus NHAs conferred notable clinical benefits in terms of decreased testosterone and PSA levels. The EMBARK study, a phase 3 study with specified LHRH-R agents, showed that combining leuprolide plus enzalutamide decreased the risk of PSA progression [hazard ratio (HR), 0.07] and improved overall survival [HR, 0.59 (immature overall survival data)] beyond that with leuprolide alone over 61 months of follow-up⁹⁸, whereas the 5-year metastasis-free survival rate was 87.3% with leuprolide plus enzalutamide. In patients with biochemical recurrence with a PSA doubling time ≤ 9 months, 88% of patients had undetectable PSA after 8 months of treatment with degarelix plus abiraterone⁹⁹.

In advanced PC, 25 weeks of goserelin plus abiraterone led to a ≥ 80% decline in PSA levels in all treated patients; 76% of patients had a PSA level ≤ 0.2 ng/mL and 98% of patients achieved testosterone levels of ≤ 50 ng/dL. Moreover, only 3.1% of patients showed radiographic progression at week 25¹⁰⁰. Other combinations of LHRH-R agonists/antagonists plus NHAs yielded similar findings, with 96% and 91% of patients with advanced PC achieving testosterone levels ≤ 50 ng/dL with relugolix plus enzalutamide or docetaxel, and leuprolide plus enzalutamide or docetaxel, respectively¹⁰¹.

Reports on specific LHRH-R agonists or antagonists plus NHAs have shown consistent efficacy in terms of decreasing PSA and testosterone levels, and preventing disease progression. However, the above studies included patients with slightly varying baseline conditions and consisted predominantly of phase 2 trials with limited sample sizes. Therefore, concluding which combination therapy with LHRH-R agonists/antagonists plus NHAs is optimal is difficult without a head-to-head comparison or studies reporting identical treatment outcomes in the same treatment setting. The clinical benefits of adding an NHA to LHRH-R agonists or antagonists are not debated. Selection among various combinations should be informed by comparison of their safety profiles, which are discussed below.

Safety profiles of LHRH-R agents plus NHAs differ among combinations but remain manageable

Whereas the safety profile of LHRH-R agonists or antagonists in combination with NHAs has been reviewed^102,103, the focus has been primarily on NHAs rather than on the specific LHRH-R agonists or antagonists used. The incidence of common adverse events observed after treatment with single-agent LHRH-R agonists or antagonists in combination with abiraterone or enzalutamide is presented in Figure 4^{91,92,95–101}. The comparison of safety profiles of these combination therapies should be interpreted with caution, because of the inclusion of various LHRH-R agonists and antagonists, various NHAs, and the limited reporting of treatment-related adverse events in some studies.

Figure 4.

Incidence of adverse events in combination therapy with LHRH-R agonists and antagonists with NHAs. Each dot represents the percentage of adverse events reported in a study; a dot at 0% indicates that the incidence was reported as 0% in the article. AST, ALT, and hypertension were defined as an adverse event of special interest in Taplin et al.⁹⁷. *Study reported only the incidence of treatment-related adverse events. ALT, alanine aminotransferase; AST, aspartate aminotransferase; LHRH-R, luteinizing hormone-releasing hormone receptor; NHA, next-generation hormonal agent (i.e., abiraterone or enzalutamide). SAE, serious adverse events; TEAEs, treatment-emergent adverse events.

Most patients treated with combination therapy comprising LHRH-R agonists or antagonists plus abiraterone or enzalutamide experienced at least 1 treatment-related adverse event (93%–100%)^{92,95,97,98,100,101}. The common adverse events (hot flushes, fatigue, headaches, hypertension, alanine transaminase increase, and aspartate aminotransferase increase) reported with the combination therapies were similar to the known adverse reactions associated with abiraterone or enzalutamide^104,105. The incidence of nausea ranged from 4% to 12% across various treatment combinations^96,98–100. In contrast, the incidence of hypertension (0%–36%)^{91,95,97,98,100,101}, diarrhea (0%–41%)^{91,92,100,101}, headaches (0%–18%)^92,97,100, and anemia (0%–52%)^95,97,100 varied widely among studies. Hyperglycemia, a known laboratory abnormality associated with abiraterone¹⁰⁵, was noted in patients treated with goserelin (10%)¹⁰⁰, leuprolide (13%–21%)^95,97, or degarelix (10%)⁹⁹ in combination with abiraterone.

Among common adverse events observed after treatment with LHRH-R agonists or antagonists plus abiraterone or enzalutamide, considerable differences have been observed in the incidence of hot flushes and fatigue among the treatment combinations (Figure 5)^92,95–101. Combination therapy containing goserelin has shown a manageable safety profile and appears to compare favorably with other LHRH-R agonists in terms of hot flushes and fatigue. Studies have reported that the incidence of hot flushes was lower with goserelin plus abiraterone (38%)¹⁰⁰ than with leuprolide plus abiraterone (80%–96%)^95,97 or leuprolide plus enzalutamide (44%–100%)^96,98,101. The incidence of fatigue was also lower with goserelin plus abiraterone (17%)¹⁰⁰ than with degarelix plus abiraterone (44%)⁹⁹, relugolix plus enzalutamide (40%)¹⁰¹, leuprolide plus abiraterone (43%–57%)^95,97, or leuprolide plus enzalutamide (18%–64%)^92,96,98,101. These findings may be particularly important for treatment selection, because fatigue and hot flushes are considered the most bothersome adverse effects of ADT, and some patients may discontinue treatment because of effects on quality of life^82,106,107.

Figure 5.

Incidence of hot flushes and fatigue associated with combination therapy comprising LHRH-R agonists and antagonists with NHAs. Incidence is rounded to whole numbers. *The study reported only the incidence of treatment-related adverse events. LHRH-R, luteinizing hormone-releasing hormone receptor; NHAs, next-generation hormonal agents (i.e., abiraterone or enzalutamide).

Although the mechanisms underlying fatigue and hot flushes associated with LHRH-R agonists or antagonists plus NHAs remain unclear, the inclusion of an AR antagonist in combination therapy has been suggested to increase the incidence of hot flushes and fatigue, which are typical effects of this drug class¹⁰⁸. In studies involving patients with any stage or advanced stage PC, the rates of fatigue and hot flushes were similar among single-agent LHRH-R agonists and antagonists in phase 3 studies^20,109,110. Previous phase 3 studies showed similar incidences of fatigue and hot flushes between ADT plus abiraterone and ADT plus placebo¹¹¹. However, ADT plus enzalutamide led to higher incidences of fatigue and hot flushes than ADT alone⁸⁸. Differences in the incidence of hot flushes among combination regimens might possibly be attributable to differences in the levels of testosterone fluctuations after treatment initiation. For example, patients who underwent orchiectomy (complete elimination of testosterone) had a lower incidence of hot flushes than those who were treated with LHRH-R agonists (rapid testosterone decrease)^61,112, and the incidence of hot flushes decreased over time with ADT¹¹³. Although the data were not collected from a single study, differences in profiles of testosterone levels in the first few days after treatment initiation have been reported among LHRH-R agonists and antagonists^112,114. The combination of goserelin and abiraterone achieves testosterone stabilization more rapidly than other combinations, thus potentially resulting in a lower incidence of hot flushes. Although the mechanism remains unclear, enzalutamide has been associated with greater risk of fatigue than abiraterone^115,116. Therefore, a combination regimen with a manageable safety profile and lower incidence of fatigue and hot flushes, such as goserelin plus abiraterone, may be an option when a combination therapy is indicated.

Concluding remarks and perspectives

Overall survival is typically considered the gold standard for evaluating cancer treatment outcomes¹¹⁷. However, many studies investigating LHRH-R agonists and antagonists in PC have focused on short-term or intermediate-term follow-up, whereas long-term survival data for this class of agents are often lacking. More than half of the studies using a single LHRH-R agonist and antagonist agent with long-term survival follow-up were conducted in patients with locally advanced PC. Among the available LHRH-R agonists and antagonists, goserelin has been extensively studied and has long-term survival data available across various stages of PC. Given that long-term survival data provide valuable insights to inform treatment decisions, therapeutic agents with data available for long-term outcomes, such as goserelin, are an important tool in the armamentarium for PC management.

LHRH-R agonists or antagonists are also commonly used in combination with NHAs for treatment of metastatic PC. However, because of the heterogeneity in study designs and the lack of head-to-head comparisons, determining the optimal combination of LHRH-R agonists or antagonists with NHAs is challenging. Because the safety profile of a therapy is an important consideration in treatment decisions, combination regimens with tolerable safety profiles, in addition to acceptable efficacy, are preferred. Because the rate of adverse events varies widely across various treatment combinations, combination regimens containing agents with manageable safety profiles, such as goserelin and abiraterone, which have been associated with diminished rates of hot flushes and fatigue, may be useful options to be considered in combination therapy. Nonetheless, further studies are warranted to provide robust evidence supporting the selection of the optimal combination therapy in various treatment settings.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Hao Zeng.

Collected the data: Jinge Zhao, Junru Chen, and Guangxi Sun.

Contributed data or analysis tools: Jinge Zhao, Junru Chen, Guangxi Sun, Pengfei Shen, and Hao Zeng.

Performed the analysis: Jinge Zhao, Junru Chen, Guangxi Sun, Pengfei Shen, and Hao Zeng.

Wrote the paper: Jinge Zhao.