Advances in the Treatment and Management of Metastatic Castration-Sensitive Prostate Cancer

Prostate cancer, one of the most common cancers diagnosed in American men, is associated with a lifetime risk of approximately 12.9%.^1,2 An estimated 288,300 new prostate cancer cases will be diagnosed in 2023, with 6 in 10 cases diagnosed in men 65 years or older (median age at diagnosis, 67 years).^1-3

Prostate cancer is the second leading cause of cancer-related death among men in the United States, accounting for approximately 34,700 deaths in 2023 and 5.7% of all cancer related deaths.^1-3 Prostate cancer is generally associated with relatively good survival rates; however, observed mortality rates tend to be higher among Black individuals and men who are 75 years or older or with advanced stage disease.² Although the majority of prostate cancer cases initially present as localized (69%) or regional (13%) tumors, approximately 8% of patients are diagnosed with de novo metastatic prostate cancer, and at least 30% will develop metastatic disease after local therapy.^2,4

Over the last decade, the overall incidence of prostate cancer has increased by 3% per year with the greatest increases seen in the number of advanced prostate cancer diagnoses (5%).^1,3,5 The 5-year survival rate is substantially lower with advanced stage prostate cancer (34.1%) compared with localized disease (100%). Thus, the need for improved treatment approaches and management strategies for patients with metastatic disease continues to grow.²

Prostate Cancer Diagnosis, Staging, and Risk Stratification

Prostate cancer staging and risk stratification schema play an important role in determining disease prognosis and helping to guide overall treatment selection. Prostate cancer is classified and staged using specific criteria established by the American Joint Committee on Cancer (AJCC); these account for 5 key factors—the extent of the primary tumor, lymph node involvement, presence of metastases, prostate-specific antigen (PSA) level upon diagnosis, and grade group based on the Gleason score.⁶ Similarly, the 2023 National Comprehensive Cancer Network guidelines for risk stratification use the presence of clinical and pathologic features (eg, primary tumor states, PSA level, and Gleason scores) to determine associated disease risk, which ranges from low to very high (Table 1).⁷

Further subclassification has been proposed for favorable high-risk disease (defined as cT1c [clinical primary tumor identified by needle biopsy found in 1 or both sides, but not palpable], grade group 8, PSA level < 10 ng/mL or cT1c, grade group 1, and PSA level > 20 ng/mL) based on data demonstrating that these patients have lower rates of prostate cancer–specific mortality at 8 years when compared with men having high-risk disease (2.1% vs 7.1%, respectively).⁸ A subsequent clinical-genomic correlative study involving 3220 men further identified a strong association between the clinical subclassification of high-risk prostate cancer (favorable, standard, or very high risk) with genomic risk markers identified using a 33-gene panel assay.⁹ Although further subclassification of high-risk disease could allow for improved personalization of therapy, it has not yet been adopted into current guidelines.⁸

Metastatic Castration-Sensitive Prostate Cancer

Metastatic castration-sensitive prostate cancer (mCSPC), also referred to as metastatic hormone-sensitive prostate cancer (mHSPC), is an advanced form of prostate cancer defined by disease that has spread from the prostate into other regions of the body and that remains responsive to hormone therapy.¹⁰ It can further be subdivided according to disease volume (high vs low) or disease risk (high vs low) according to established risk criteria that take into account the presence of bone or visceral metastases and the associated Gleason score. Risk criteria most commonly used for classification are derived from the CHAARTED (NCT00309985) and LATITUDE (NCT01715285) trials (Table 2).^11,12

First-Line Treatment Approaches for mCSPC

Doublet Therapy

Surgery and radiotherapy (RT) are the mainstay of treatment for localized disease, but androgen-deprivation therapy (ADT), androgen receptor-signaling inhibition (ARSI), and chemotherapy (eg, docetaxel) constitute standard of care (SOC) for patients with recurrent or metastatic disease. Following the results of early research showing that prostate cancer is an androgen-driven disease that responds to testosterone deprivation, ADT using testosterone suppression with or without AR inhibition was established as the SOC treatment for mCSPC in the early 1940s.¹⁰ Early data from the TAX 327 and SWOG9916 trials demonstrated a potential survival benefit with the addition of cytotoxic therapy (docetaxel) to ADT, which initiated a shift toward doublet therapy as a preferred treatment approach.^10,13,14

Subsequent study data have since established 2 distinct doublet therapy approaches as new SOC treatments in mCSPC. ADT plus docetaxel for 6 cycles is considered an SOC treatment approach for high-volume mCSPC based on results of the GETUG-AFU 15 (NCT00104715), CHAARTED, and STAMPEDE (C arm) (NCT00268476) studies, which demonstrated a prolonged survival benefit among patients with mCSPC and particularly those with high-volume metastatic disease.^10,11,15-17 Based on findings from the LATITUDE and STAMPEDE (arm G) trials, doublet therapy with ADT plus abiraterone acetate continues until disease progression is considered a SOC regimen for all patients with mCSPC.^12,17,18

Predictive biomarkers to help guide treatment selection between available doublet therapies are needed. However, use of ADT plus docetaxel may be preferred for patients with mCSPC who have more than 4 metastatic lesions, good performance status, and a desire for shorter treatment duration. Alternatively, ADT plus abiraterone acetate, an androgen receptor pathway inhibitor (ARPI), may be better suited for patients who have fewer than 4 sites of metastases or who are unable to tolerate chemotherapy.¹⁷

ARPI-Based Doublet Therapy
Clinical trials investigating next-generation ARPIs (enzalutamide, apalutamide, darolutamide) plus ADT have further expanded available doublet therapy approaches for patients with mCSPC in the first-line setting. A summary of key efficacy and safety end points from select trials evalu­ating double therapy approaches appears in Table 3.^12,19-23

ARCHES

In the randomized, phase 3 ARCHES trial (NCT02677896), the addition of enzalutamide or placebo to ADT was eval­uated in men with de novo or recurrent mCSPC.¹⁹ Of the 1150 study participants, 63.2% had high-volume disease, and 17.9% had received prior therapy with docetaxel.¹⁹

At a median follow-up of 14.4 months, radiographic dis­ease progression was noted in 15.9% of patients receiving enzalutamide plus ADT vs 34.9% placebo plus ADT, and the addition of enzalutamide to ADT significantly reduced the risk of radiographic disease progression or death by 61% (HR, 0.39; 95% CI, 0.30-0.50; P < .001) compared with placebo.19 Upon follow-up analysis of survival data, use of enzalutamide plus ADT led to a 34% reduction in the risk of death vs placebo plus ADT (HR, 0.66; 95% CI, 0.53-0.81; P < .001) with an associated survival benefit demonstrated across most patient subgroups.²⁰

Frequently reported adverse events (AEs) of any grade are listed in Table 3.^12,19-23 AEs of grade 3 or greater were similar between treatment arms, with hypertension most frequently reported (3.3% in the enzalutamide arm vs 1.7% in the placebo arm). AEs leading to treatment dis­continuation occurred in 7.2% of patients who received enzalutamide plus ADT vs 5.2% of those given placebo.¹⁹

TITAN

In the randomized, phase 3 TITAN trial (NCT02489318), doublet therapy with ADT plus either apalutamide or pla­cebo was evaluated in men with mCSPC.21 Of 1052 partici­pants included in the study, approximately 63% of patients were classified as having high-volume disease according to CHAARTED trial criteria.²¹

Final survival data demonstrated that doublet therapy with apalutamide was associated with a 35% lower risk of death than noted with use of placebo (HR, 0.65; 95% CI, 0.53-0.79; P < .0001), which was deemed significant. At 48 months of follow-up, overall survival (OS) was 65.1% in the apalutamide group vs 51.8% placebo, with favorable OS benefits observed across prespecified subgroups, in­cluding patients with high-risk, either high- or low-volume disease.²² Apalutamide use also was related to a 52% lower risk of radiographic progression.²¹

The incidence of serious AEs of grade 3 or greater did not differ significantly between the apalutamide and pla­cebo treatment arms, with hypertension being the most frequently reported grade 3 AE (8.4% vs 9.1%, respective­ly). Treatment discontinuation secondary to AEs occurred in 8% vs 5.3% of patients, respectively.²¹

LATITUDE

In the phase 3 LATITUDE trial, the addition of abiraterone acetate and prednisone (AAP) or placebo to ADT was eval­uated in 1199 men with high-risk mCSPC. Interim data at 3 years demonstrated an OS rate of 66% in the AAP group vs 49% in the placebo group.¹² When compared with pla­cebo, AAP use also resulted in a 38% lower relative risk of death and a 53% lower relative risk of radiographic disease progression.¹² Upon final analysis, AAP demonstrated a continued survival benefit with a longer median survival compared with placebo (53.3 vs 36.5 months, respective­ly). OS benefit was seen across most patient subgroups, with the exception of patients with a performance status of 2 and those with a Gleason score of less than 8.²³

Patients given AAP and those given placebo had similar overall incidences of treatment-related AEs (TRAEs) (95% vs 93%, respectively). Grade 3 mineralocorticoid-related AEs of special interest occurred more frequently in patients receiving AAP vs those given placebo, with hypertension (21% vs 10%) and hypokalemia (12% vs 1%) most report­ed. Treatment discontinuation due to TRAEs occurred at a rate of 4% in the AAP group vs 2% in the placebo group.²³

ARPI-Based Triplet Therapy in mCSPC

The treatment landscape for mCSPC has continued to evolve in recent years as outcomes of various phase 3 randomized controlled trials (RCTs) demonstrated favorable survival outcomes using ARPI-based triplet therapy approaches. In 2022, data reported from 2 phase 3 RCTs showed an OS benefit for ARSI-based triplet therapy compared with dou­blet therapy with docetaxel plus ADT, demonstrating the value of intensive early treatment in mCSPC. Investigators involved in the ARASENS trial (NCT02799602) evaluated the addition of darolutamide to docetaxel plus ADT.^24,25 In the PEACE-1 trial (NCT01957436), the addition of AAP to docetaxel plus ADT was evaluated.²⁶ Results of the ENZAMET study (NCT02446405) further demonstrat­ed a clear OS prolongation with concurrent use of early docetaxel and enzalutamide plus ADT.^27,28 Table 4 shows a summary of key efficacy and safety data from select trials evaluating triplet therapy approaches.^25-29

ENZAMET

In the phase 3 ENZAMET trial, the addition of enzalut­amide or placebo to ADT with or without early docetaxel was evaluated. In all, 52% of the 1125 study participants were classified as having high-volume mCSPC.²⁷ At 5-year follow-up, OS and clinical PFS rates were higher in the enzalutamide group than in the placebo group (OS, 67% vs 57%; PFS, 56% vs 28%), respectively. Moreover, the risk of death was 33% lower in the enzalutamide group than in the placebo group. OS and PFS (PSA and clinical) benefits were consistent across subgroups.²⁸

The most common AEs of grade 3 or greater not con­sidered to be associated with concurrent docetaxel were hypertension (10%) and fatigue (6%). AE-related treat­ment discontinuation occurred in 11% of patients in the enzalutamide group vs 5% of those given placebo.²⁸

ARASENS

The international, randomized, phase 3 ARASENS trial as­sessed a triplet therapy approach in which darolutamide or placebo was given in combination with ADT plus docetaxel in men with mHSPC. The study included 1306 participants, of whom 77% had high-volume disease and 70% had high-risk disease.^25,29

With a median treatment duration of 41 months, triplet therapy with darolutamide reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .001). Reported OS at 4 years was 62.7% in the darolutamide group vs 50.4% for those given placebo, and it was consistent across most subgroups.²⁵ Subsequent subgroup analyses by disease volume and risk further revealed an OS benefit among pa­tients with high-volume disease (HR, 0.69; 95% CI, 0.57- 0.82) and high-risk disease (HR, 0.71; 95% CI, 0.58-0.86).²⁹

Common AEs, many of which are known docetaxel-related toxicities, occurred most frequently during periods of docetaxel treatment (Table 4).^25,29 AE-associated treat­ment discontinuation was reported in 13.5% of patients in the darolutamide group vs 10.6% of patients in the placebo group.²⁵

PEACE-1

The addition of AAP to ADT with or without docetaxel and with or without RT was evaluated in the randomized, phase 3 PEACE-1 trial, which included 1173 patients with de novo mCSPC. Treatment was stratified according to study site, performance status, extent of disease burden based on metastatic status (lymph node vs bone vs visceral), and disease volume (high vs low).²⁶

The addition of AAP to ADT with or without docetaxel and with or without RT extended radiographic PFS (rPFS) by a median of 2.1 years and OS by a median of 0.9 years. As­sociated survival benefits were seen across most subgroups, with a pronounced increase in OS observed among patients with high-volume metastatic burden (median, 1.1 year) (HR, 0.72; 95.1% CI, 0.55-0.95; P < .019).26 However, data from a post-hoc analysis showed that survival benefits asso­ciated with abiraterone use may decrease progressively with age, with decreased rPFS and OS reported among men aged 70 years or older.³⁰

Among patients treated with AAP vs those who were not, the incidence of severe AEs of grade 3 or greater were similar; however, patients in the AAP arm more frequently experienced hypertension (22% vs 13%) and hepatotoxic­ity (increased aminotransferase levels, 6% vs 1%).²⁶

Doublet vs Triplet Therapy in mCSPC

There is a lack of RCTs directly comparing available trip­let and doublet therapies; however, several meta-analyses have been conducted to gain greater insights for treatment selection and personalization of therapy. Results of a me­ta-analysis comparing data from the TITAN, ARCHES, ENZAMET, PEACE-1, and ARASENS trials showed that triplet therapy reduced the risk of death by 27% when compared with doublet therapy (ADT plus docetaxel) (HR, 0.73; 95% CI, 0.65-0.83; P < .00001).³¹

Pooled HR data assessed in another meta-analysis also revealed a significant reduction in the risk of death with the addition of an ARPI to ADT plus docetaxel (HR, 0.74; 95% CI, 0.66-0.84; P < .00001).³² The OS effect was greater among patients with high-volume disease and synchro­nous (de novo) disease using a concomitant vs sequential treatment strategy, suggesting a potential for greater OS benefit using a triplet therapy approach in patients with de novo metastatic disease.⁴ More recent meta-analysis data demonstrated that intensified treatment with triplet therapies can offer improved OS compared with ADT plus docetaxel; however, no significant difference in OS with ARPI-based doublet therapy was noted, suggesting that ARPI-based doublet therapy is a safer treatment option that offers comparable efficacy.³²

Considering currently available data, the general con­sensus among some groups of experts is that a first-line triplet therapy approach may be most appropriate for fit and younger patients with synchronous mCSPC. When a triplet therapy approach is not feasible, a doublet approach with ADT plus docetaxel or ADT plus ARPI is appropriate with comparable efficacy.³³

Considerations for Health-Related Quality of Life and Patient Outcomes With Treatment Selection in mCSPC

Although OS and efficacy are key factors in guiding treat­ment selection, toxicity profiles of individual therapeutic agents and their impact on a patient’s overall quality of life (QOL) are important to consider.

Findings reported in a 2023 systematic review that included data from 6 randomized control trials (ARCHES, ENZAMET, TITAN, STAMPEDE, LATITUDE, and ARASENS) demonstrated that doublet therapy with ARSIs plus ADT increases overall health-related QOL (HRQOL) for patients with mCSPC and prolongs time to first dete­rioration into pain or fatigue compared with ADT given alone or with first-generation nonsteroidal antiestrogens or docetaxel.³⁴

HRQOL Data From Key Clinical Trials Evaluating ARPI-Based Treatment in mCSPC

Enzalutamide

HRQOL data from the ARCHES trial showed that use of enzalutamide significantly delayed time to first clinically meaningful deterioration (TTFD) for worst pain (14.09 vs 11.10 months; HR, 0.82; P = .032), pain severity (19.38 vs 16.76 months; HR, 0.79; P = .021), and EuroQoL 5-Dimensions, 5 Levels (EQ-5D-5 L) visual analogue scale (VAS) score (11.14 vs 8.38 months; HR, 0.80; P = .0070) when compared with patients who were given placebo.³⁵ According to subgroup analyses by disease volume (high vs low), among patients classified according to CHAARTED criteria, those with high-volume mCSPC had a significant delay in deterioration for several HRQOL subscales and pain severity, but those with low-volume disease had only a modest delay.³⁵

HRQOL data from the ENZAMET trial revealed that at 12 weeks, scores deteriorated more for patients in the enzalutamide group than in the placebo group. Use of placebo was favored over enzalutamide therapy when dif­ferences in overall means for fatigue (5.2; P < .001), cog­nitive function (4.0; P < .001), and physical function (2.6; P <.001) were considered, but this was not noted for overall health and QOL (OHQL) (1.2; P = .1). After 6 months, the enzalutamide group saw greater HRQOL benefits. Deterioration-free survival rates at 3 years and log-rank P values comparing the whole distributions favored enzalut­amide therapy over use of placebo for OHQL (31% vs 17%; P < .0001), cognitive function (31% vs 20%; P = .001), and physical function (31% vs 22%; P < .001) but not for fatigue (24% vs 18%; P = .16).³⁶

A systematic review of HRQOL data from the ARCHES, PROSPER (NCT02003924), PREVAIL (NCT01212991), and AFFIRM (NCT00974311) trials further demonstrated that enzalutamide therapy slowed deterioration of overall HRQOL across the prostate cancer continuum, includ­ing in men diagnosed with mCSPC and those who devel­oped castration-resistant disease. Benefits in terms of pain mitigation and decreased symptom burden were greatest among patients with advanced disease.³⁷

Apalutamide

Patient outcomes and HRQOL data from the TITAN trial showed apalutamide therapy to be associated with a longer median time to worst pain intensity progression than noted with use of placebo, but the difference failed to achieve statistical significance (19.09 vs 11.99 months; HR, 0.89; 95% CI, 0.75-1.06; P = .20).³⁸ Functional Assessment of Cancer Therapy-Prostate (FACT-P) total scores demon­strated no significant difference in preserved HRQOL, with a median time to deterioration of 8.87 months in the apa­lutamide group vs 9.23 months in the placebo group (HR, 1.02; 95% CI, 0.85-1.22; P = .85). The EQ-5D-5L VAS scores remained stable between both treatment groups.³⁸

Patient-reported outcomes data showed that pain and fatigue remained stable or improved during treatment in both arms, with greater improvements seen among patients with higher baseline severity scores.³⁹

Final analysis of HRQOL data from the TITAN trial were consistent with earlier findings, showing no signifi­cant differences between treatment arms in median time to deterioration in any Brief Pain Inventory or FACT-P scores and no notable worsening of scores over time in either group. Moreover, reported energy levels remained stable or improved with each cycle for more than 78% of patients receiving apalutamide and more than 71% of those given placebo.⁴⁰

Darolutamide

HRQOL data specifically accessing the effects of darolut­amide for patients with mCSPC is relatively limited com­pared with those with mCRPC; however, outcomes data reported in the ARASENS trial demonstrated that patients receiving darolutamide had significantly longer times to pain progression (HR, 0.79; 95% CI, 0.66-0.95; P = .01) and first symptomatic skeletal event (HR, 0.71; 95% CI, 0.54-0.94; P = .02). Patients in the darolutamide arm also showed a prolonged time to a symptomatic skeletal event-free survival (HR, 0.61; 95% CI, 0.52-0.72; P < .001).²⁵

Abiraterone and Prednisone

According to HRQOL data from the LATITUDE trial, the addition of AAP to ADT consistently improved pain and fatigue symptoms and overall HRQOL in men with high-risk mCSPC when compared with those given placebo.⁴¹ Men treated with AAP plus ADT had a significantly longer median time to worst pain intensity progression, worst fatigue intensity progression, and functional deterioration status as demonstrated by FACT-P total scores (AAP, 12.9 months; placebo, 8.3 months) (HR, 0.85; 95% CI, 0.74-0.99; P = .032). Median time to deterioration of well-being was also prolonged in the AAP arm, although median time to deterioration of functional, emotional, and social/family well-being did not substantially differ between treatment arms.⁴¹

Findings from the STAMPEDE tri­al further demonstrated improved HRQOL with the addition of AAP to SOC ADT as shown by higher associat­ed Global-QOL scores at 1 year (+5.7 points) and 2 years (+3.9 points) of follow-up.⁴² Although observed differ­ences were both statistically significant, only the difference seen at 1 year was considered to be a clinically meaningful difference (ie, predefined threshold of > 4 points).⁴²

Shared Decision-Making in mCSPC

The shared decision-making process involves active par­ticipation of patients and their health care providers in selecting the best treatment option based on the patient’s individual needs and preferences. However, assessing indi­vidual preferences and values can be challenging. Although no formal process exists, patient-centric decision aids have been developed to enable patients to provide information and input into the treatment decision-making process.

Decision aids allow systematic assessment and incorpo­ration of patient preferences and values to rank potential treatment options by likelihood of achieving the preferred outcome. A preference-based approach may help patients through their decision-making process, potentially affect­ing adherence to treatment, tolerance of AEs, and satisfac­tion with the decision.⁴³

Future Perspectives

As progression to castration resistance is an adaptive process, ongoing efforts to assess the benefits of deinten­sification and adaptive treatment strategies continue. In­termittent therapy approaches have been investigated to minimize treatment exposure, thereby reducing the poten­tial for AEs and improving HRQOL. More recently, there has been a growing interest identifying response-based end points that could help guide adaptive treatment strategies. However, a lack of conclusive data with some clinical trials has led to some heterogeneity in treatment practices. Future research is needed to shed further light on this subject.¹⁰

With an increased number of deleterious genetic alter­ations correlating with progression from localized to ad­vanced prostate cancer, there is a growing interest in iden­tifying novel biomarkers that may help to better inform treatment decision-making and expand the understanding and development of personalized and targeted therapies for mCSPC.

Advancements in the treatment of prostate cancer have led to improved survival, especially in patients with syn­chronous, high-volume disease.¹⁰ How­ever, novel treatment approaches that improve personalization of therapy and decrease the unbalanced burden of ad­vanced disease are still needed.¹⁰

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