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The Rapidly Evolving Management Strategy Of Metastatic Hormone-Sensitive Prostate Cancer

Prostate cancer (PCa) is the most common non-cutaneous malignancy in US men and the second most common cause of cancer-specific death.1 The American Cancer Society estimates that in 2019, approximately 174,650 new cases will be diagnosed, and 31,620 cancer-specific deaths will occur.2  Localized potentially curable PCa is unequivocally the most commonly diagnosed disease, but recent evidence suggests that the incidence of de novo metastatic disease is gradually rising.3 This could be a result of decreased prostate-specific antigen (PSA) screening over the last several years. In 2012 the United States Preventative Services Task Force (USPSTF) recommended against PSA screening (Grade D recommendation),4 later changing it to grade C in 2018.5 Furthermore, many PCa patients treated for localized disease will ultimately progress to develop recurrence and metastatic disease.6 Metastatic disease occurs in approximately a third of PCa patients,7 with the most common sites being bone (84%), distant lymph nodes (10.6%), liver (10.2%), and thorax (9.1%), with 18.4% of patients manifesting metastases in multiple sites.8 Generally, PCa has an overall 5-year survival rate of 98.2%, but metastatic disease has a dismal 30% 5-year survival rate.9

Conventional treatment of metastatic PCa has been androgen deprivation therapy (ADT) since the landmark discovery by Huggins and Hodges in 1941, who later received the Nobel prize for this discovery. They found that PCa metastases were hormonally sensitive, defining this stage of disease as metastatic hormone-sensitive PCa (mHSPC).10 The mainstay of hormonal treatment is to achieve castrate levels of testosterone with either bilateral orchiectomy or through the use of ADT which is mainly composed of a gonadotropin-releasing hormone (GnRH) analog or antagonists (Figure 1). Unfortunately, mHSPC treated with ADT eventually transitions to the castrate-resistant PCa (CRPC) state, defined by disease progression despite ADT with castrate testosterone levels and may present as either a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases.11 CRPC has a median survival of approximately three years12 and is also associated with a quality of life deterioration.13 Approaches to improve the response rate to ADT and/or decrease its associated side effects in mHSPC have included intermittent hormonal therapy, adding an antiandrogen with medical or surgical castration, or treating with antiandrogens alone.14 However, the benefit of these approaches resulted in a low improvement rate of only 2-3% in the 5-year survival rate.14

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In recent years, several systemic therapies have been introduced in the mHSPC space, some of which had been previously reserved only for metastatic CRPC (mCRPC). These treatments, introduced earlier in the disease spectrum, have demonstrated significant efficacy and tolerability in mHSPC.16-18 Furthermore, there is expanding data demonstrating the beneficial role of treating the primary tumor in these patients,19-21 and also treating specific metastatic sites.22, 23 The specific role of “cytoreductive” therapy and metastases directed therapy in oligometastatic PCa is beyond the scope of this review and will be discussed elsewhere (“Oligometastatic Prostate Cancer – Cytoreductive treatment and metastasis directed Therapy”). 

Since 2015 there have been several landmark studies introducing new therapies in addition to ADT in the mHSPC space, showing significant overall survival (OS) improvement. As this is a dynamic and rapidly changing field, this review will summarize all recently added therapies and discuss their use and benefits, in addition to mentioning ongoing and future trials.

Chemotherapy in mHSPC


Early studies of chemotherapy combined with ADT did not show an OS benefit. This was partly due to toxicity and lack of active agents, including ketoconazole, doxorubicin, vinblastine, and estramustine.24 These agents did not confer an OS advantage, and 51% of the patients had experienced grade 3 or worse adverse events.24 Other assessed medications did not show any benefit either, including mitomycin, cyclophosphamide, epirubicin, and fluorouracil.25 Only in 2004, after docetaxel chemotherapy had shown improved survival in CRPC patients,26 researchers considered adding this specific treatment when ADT was initiated in mHSPC patients. 

The GETUG-AFU 15 French trial was the first phase 3 study assessing the effect of 9 cycles of docetaxel chemotherapy for mHSPC27 (Figure 1). This trial did not show a beneficial OS effect but did demonstrate significant chemotherapy-associated morbidity. Post hoc analyses of these data did, however, suggest a trend toward a survival benefit in men with high-burden mHSPC, (HR 0.78, p = 0.14).28 Later, in 2015 the US-led Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial randomized 790 mHSPC patients to ADT with or without six cycles of docetaxel16 (Figure 2). This was the first trial showing the association between docetaxel and improved OS with a 13.6 months advantage (HR 0.61, p<0.001). Importantly, the trial showed that only men with high-burden metastatic disease (presence of visceral metastases, or ≥4 bone lesions with ≥one beyond the axial skeleton) had an OS benefit in the pre-planned subgroup analysis (HR 0.60, 95% CI 0.45–0.81). These findings were validated in a longer median follow-up report of 53.7 months (HR 0.63, p<0.001).24 Importantly, the benefit in this long-term follow-up report was consistent across all subgroups with two notable exceptions: Patients with a low disease burden (HR 1.04, 95%CI 0.7-1.55) and those who had prior local therapy (HR 0.97, 95%CI 0.58-1.56).24

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Another similar trial was arm C of The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) UK-led trial. This trial compared six cycles of docetaxel to standard ADT in men with mHSPC or locally-advanced disease17(Figure 3). The chemotherapy conferred a clear median OS advantage of 10 months (81 vs. 71 months, HR 0.78, p = 0.006), and median progression-free survival (PFS) advantage of 17 months (HR 0.61, p<0.001).17 This trial also showed that adding zoledronic acid alone to ADT did not show an OS benefit.17 These results were supported by a metanalysis validating the role of early docetaxel for mHSPC.29 Currently, most urological and oncological guidelines recommend the use of docetaxel in addition to ADT in mHSPC fit patients as one of the standard therapies for newly diagnosed metastatic disease.

Lastly, quality of life had decreased after three months of chemohormonal therapy (compared to ADT alone) in all three mentioned trials. In GETUG-AFU 15 and CHAARTED the most common grade 3 or greater adverse events included neutropenia (32% and 12%), febrile neutropenia (7% and 6%), and fatigue (7% and 4%), respectively. In STAMPEDE, the grade 3 or greater adverse events rates were 52% vs. 32% of patients.  However, after 12 months this had improved, and there was a 10% balanced rate of grade 3 or greater adverse events in both arms.30 This is now regarded as the standard of care for mHSPC, in men who are healthy enough to receive this therapy and especially in high-burden metastatic disease.31


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Abiraterone and prednisone in mHSPC


In 2017, two years after chemohormonal therapy was shown to significantly benefit mHSPC patients, Abiraterone acetate, an antiandrogen medication, was also assessed in this disease space in two separate trials. Approval of this drug in the pre-chemotherapy and post-chemotherapy era led to its application in earlier disease. The G arm in the STAMPEDE trial specifically analyzed whether the addition of Abiraterone and 5 mg prednisolone to ADT would have an OS advantage.18 Over a median follow-up time of 40 months, Abiraterone + prednisolone and ADT conferred a 37% relative OS improvement when compared to ADT and placebo (HR 0.63, 95%CI 0.52-0.76, p<0.001).18 Additionally, the Abiraterone arm showed a 71% improvement in failure-free survival  (HR 0.29, 95%CI 0.25-0.34) as well as significantly decreasing skeletal-related events (SRE) among the entire cohort (HR 0.46, 95%CI 0.37-0.58), and specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58).18

The second trial published in 2017 was the LATITUDE trial, which was a multinational (235 sites at 34 countries) phase 3 study that enrolled high-risk mHSPC patients only (having at least two of the following: Gleason score of ≥ 8, ≥ 3 bone metastases, or the presence of visceral metastases) and assessed the role of Abiraterone in these patients32 (Figure 4). After a median follow-up time of 30.4 months, an OS advantage of 17% in the Abiraterone +ADT arm compared to ADT + placebo arm was shown with an HR almost identical to that of STAMPEDE (66% vs. 49%, HR 0.62, p<0.001).32 Based on these results, Abiraterone gained FDA approval in February 2018 for the treatment of high-risk mHSPC, expanding its indication beyond the 2012 approval for mCRPC. Both STAMPEDE AND LATITUDE trials also showed benefit in radiologic- and PSA progression, and PCa-specific mortality (PCSM).18, 32

figure-5-LATITUDE-study2x.jpg
Interestingly, post hoc analyses of the LATITUDE trial demonstrated that Abiraterone was beneficial both in low- and high-burden metastatic disease (using the CHAARTED criteria)16 with an HR 0.66, p = 0.041 and HR 0.54, p<0.001, respectively.33 Additionally, the LATITUDE trial presented patient-reported outcomes showing improvement in time until pain progression (HR 0.63, p<0.001), longer time to worsened fatigue intensity (HR 0.65, p = 0.001), and longer time to deterioration of functional status (HR 0.85, p=0.032).34 Lastly, Abiraterone did not confer any safety and toxicity issues.35

At the GU-ASCO 2019 annual meeting, Dr. Kim N. Chi presented the results of the final analysis of the LATITUDE trial conducted after a median follow up of 51.8 months.36 A total of 618 deaths were observed, and 26.3% of patients in the Abiraterone arm remained on therapy. Abiraterone plus prednisone continued to show a median OS benefit over placebo (53.3 vs. 36.5 months, HR: 0.7, 95% CI: 0.6-0.8; p<0.0001). Secondary endpoint analyses showed that Abiraterone outperformed placebo in all categories, including pain progression, SRE, chemotherapy initiation, subsequent therapy, and progression to subsequent therapy or death.36 Based on the CHAARTED16 definition of high-burden metastatic disease, patients with high-burden disease derived the most benefit (HR 0.62, 95% CI 0.52-0.74, p<0.0001) compared to those with a low-burden disease (HR 0.72, 95% CI 0.47-1.10, p=0.124). In terms of toxicity and adverse events, 21.9% of patients on abiraterone had hypertension, 11.7% had hypokalemia, 8.9% had hepatoxicity, and 3.9% had a cardiac disorder.36

Enzalutamide in mHSPC


Enzalutamide is a selective non-steroidal androgen receptor (AR) antagonist that has shown OS benefit in CRPC. Unlike the first-generation non-steroidal bicalutamide, enzalutamide does not promote translocation of the AR to the cell nucleus and also prevents binding of the AR to DNA and AR coactivator proteins.37 There has been an ongoing effort to establish the efficacy of Enzalutamide in the mHSPC disease space. As both Enzalutamide and Abiraterone had similar outcomes when utilized in later disease states (CRPC), it was not unreasonable to expect similar outcomes when utilized earlier in the disease. In 2019 two large international phase 3 prospective randomized trials assessing the role of Enzalutamide in the mHSPC space were published. 

The first one was the multinational ARCHES trial in which 1150 men with mHSPC were randomized to treatment with ADT plus Enzalutamide or placebo38 (Figure 5). Patients were stratified by disease volume (based on CHAARTED16 criteria) and prior docetaxel therapy. Approximately 18% of patients in each arm had also received treatment with docetaxel. The risk of radiographic progression or death was significantly reduced with Enzalutamide compared to the placebo arm (median not reached vs. 19.0 months, HR 0.39, 95% CI, 0.30-0.50, p<0.001;). Additionally, Enzalutamide significantly reduced the risk of PSA progression, initiation of new antineoplastic therapy, first symptomatic SRE, CRPC, and reduced risk of pain progression (p<0.001). Similar impressive improvements were noted in all prespecified subgroups stratified by disease volume and prior docetaxel therapy. Unfortunately, OS data were still immature at the time of publication, with only 84 deaths been reported (Enzalutamide, n=39 vs. placebo, n=45; with median OS duration not reached in both arms, HR 0.81; 95% CI, 0.53-1.25; p=0.3361).38 Patients in both treatment groups reported a high baseline level of quality of life, maintained over time. Lastly, grade 3 or greater adverse events were reported in 24.3% of patients in the Enzalutamide arm vs. 25.6% of patients in the placebo arm,38 consistent with the safety profile of Enzalutamide shown in previous clinical trials in the CRPC setting.

figure-6-ARCHES-trial2x.jpg
The second international phase 3 trial was the Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) study, in which men with mHSPC received ADT with or without docetaxel, and were also randomized to treatment with Enzalutamide or non-steroidal anti-androgen39 (Figure 6). ENZAMET is the first mHSPC trial to report OS data and outcomes of Enzalutamide + ADT in patients who also received concurrent docetaxel. A total of 1125 patients were randomly assigned 1:1 to ADT plus either Enzalutamide or a non-steroidal anti-androgen. Randomization was stratified by disease volume (using CHAARTED16 criteria), planned early docetaxel, planned anti-resorptive therapy, comorbidity score, and study site. In the non-steroidal anti-androgen arm, 44% of patients were planned for early docetaxel, compared to 45% in the Enzalutamide arm. Also, 53% of patients in the non-steroidal anti-androgen arm had high-burden metastatic disease, compared to 52% in the Enzalutamide arm. OS was significantly prolonged in the Enzalutamide arm compared to the non-steroidal anti-androgen arm (HR 0.67, 95% CI 0.52-0.86).39 Additionally, time to PSA rise, clinical progression, or death (HR 0.39, 95% CI 0.33-0.47) and time to clinical progression (HR 0.40, 95%CI 0.33-0.49) both favored Enzalutamide.39 In the prespecified subgroup analysis based on receipt of docetaxel, Enzalutamide significantly improved time to clinical progression (HR 0.48, 95%CI 0.37-0.62), but did not improve OS (HR 0.90, 95%CI 0.62-1.31) among men who received docetaxel. However, in men who did not receive docetaxel, Enzalutamide improved clinical progression (HR 0.34, 95%CI 0.26-0.44) and OS (HR 0.53, 95%CI 0.37-0.75).39 Serious adverse events occurred in 42% of patients in the Enzalutamide arm, compared to 34% in the non-steroidal anti-androgen arm.39 Increased toxicity was shown with the addition of Enzalutamide, as expected, and patients who were also treated with docetaxel experienced more chemotherapy-related toxicity.

figure-7-ENZAMET-trial2x.jpg

Apalutamide in mHSPC


Apalutamide is an oral nonsteroidal anti-androgen, which similarly to Enzalutamide, binds directly to the ligand-binding domain of the AR and prevents AR translocation, DNA binding, and AR-mediated transcription.40 Apalutamide has shown benefit over placebo in the non-metastatic CRPC setting in the SPARTAN phase 3 placebo-controlled trial.41 Published in 2019, the Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study is an international phase 3 trial randomizing 1052 mHSPC patients to treatment with ADT with or without Apalutamide42 (Figure 7). A total of 11% of patients had prior docetaxel treatment, and most patients had high volume disease (63%). Median radiographic PFS (rPFS) was 22.1 months in the placebo group and not yet reached in the Apalutamide group.42 Apalutamide improved OS (HR 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death while median OS had not yet been reached. The OS benefit was also consistent through all subgroups. Based on these results, the independent data monitoring committee recommended allowing crossover of patients from the placebo arm to the Apalutamide arm.42 At two years, there was a 20% difference in the rate of rPFS, with 68% of patients in the Apalutamide arm being free of progression.  Secondary and exploratory endpoints also favored Apalutamide, with 75% of patients remaining free from PSA progression at two years with Apalutamide. Only 8% of patients taking Apalutamide discontinued due to adverse events, and largely due to a grade 1 or 2 rash, occurring in 37% of patients.42

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Comparison of treatments - which treatment to choose?


Since 2015 several medications have been shown to have significant benefits in the mHSPC space (Figure 10). However, no prospective trial has randomized men with mHSPC to ADT plus any of the mentioned treatments. However, in the STAMPEDE trials, there was a period of simultaneous enrollment in arm C (chemohormonal therapy) and arm G (Abiraterone), and a post hoc analysis comparing outcomes between these arms was reported.43 Abiraterone was associated with longer failure-free survival (HR 0.56, p<0.001) and PFS (HR 0.69, p=0.023) due to ongoing AR–directed treatment as failure was driven by rising PSA. However, no significant difference was shown between these arms in terms of symptomatic SRE rate (HR 0.82, p=0.648), OS (HR1.13, p=0.691), or PCSM (HR 1.05, p=0.620).43 A recently published network meta-analysis indirectly compared two therapeutic options (ADT + docetaxel to ADT + Abiraterone) by using a common comparator arm.44 This network meta-analysis used data from the GETUG-AFU 15, CHAARTED, LATITUDE, and STAMPEDE trials. Overall, 6,067 patients were included: 1,181 (19.5%) received ADT+docetaxel, 1,557 (25.7%) received ADT + Abiraterone, and 3,329 (54.9%) received ADT alone.44 The pooled HR for OS demonstrated a benefit for docetaxel and Abiraterone compared to ADT alone. However, the indirect comparison of both these treatment strategies demonstrated no statistically significant OS difference (HR 0.84, 95%CI 0.67– 1.06).44 These trials ultimately suggest that as the data currently stands, both therapeutic options are acceptable in the mHSPC space.

figure-9-proven-treatment2x.jpg
However, on a more practical note, docetaxel can be offered to mHSPC patients eligible for chemotherapy, with a high metastatic burden or rapid disease progression.16 In contrast, docetaxel should probably not be given to patients with advanced age, poor performance status, significant comorbidities, and based on patient preference.13 Abiraterone has a better side effect profile than docetaxel, it is easier to administer, with only 12% of patients discontinuing therapy due to toxic effects, and only 12% reported to have dose modification in the LATITUDE trial.32 However, treatment duration with Abiraterone is longer at two years or more. This raises potential concerns about safety, especially in patients with pre-existing risk factors for cardiovascular disorders and stroke.13 Docetaxel, given as a short course might be preferred in patients with good performance status to avoid the feared long-term effects of steroids and the Abiraterone-associated toxicity (hyperglycemia, cardiovascular risks, osteopenia and/or osteoporosis).13 Moreover, the mandatory need for concurrent prednisone treatment with Abiraterone can potentially limit its use in brittle diabetes, chronic gastric ulcers, and any existing infection.13

Data is currently insufficient to make any recommendations on when it is preferable to give Enzalutamide or Apalutamide. However, these should be avoided in men with central nervous system disorders, and especially people with seizure disorders.45 A summarized table aiming to aid in choosing the appropriate treatment for mHSPC is shown in Table 1, while Table 2 summarized the main results of the various trials mentioned since 2015.

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Another important issue to consider when deciding which treatment is appropriate is its cost. While the cost of a 6-cycle docetaxel course is estimated to be about $20,000, the cost of Abiraterone for a 2-year course can exceed $120,000 per patient.46 Importantly, cost analyses for Abiraterone have only been done in the CRPC setting, and they could be substantially different in the mHSPC setting, and difficult to predict.13 No long-term cost analysis for Enzalutamide and Apalutamide has been published to this date.  

It is noteworthy, that in patients with low-burden metastatic disease or significant comorbid conditions, ADT alone remains a valid treatment option, which should be discussed with the patient.13 Furthermore, the question of whether the combination of various systemic treatments might lead to an additive OS benefit is unclear. A partial response to this question will be provided from the ongoing PEACE1 (Phase III Study for Patients with Metastatic Hormone-naïve Prostate Cancer) trial (NCT01957436), assessing the combination of Abiraterone and docetaxel in one of its study arms.

Ongoing and future trials

Multiple ongoing trials are currently assessing combination of systemic therapies and novel medications in the mHSPC space. These include:

  1. The PEACE-1 trial is a four-arm prospective randomized controlled trial in which 916 men with mHSPC are randomized to four possible arms and treated with ADT and docetaxel with or without abiraterone, and with or without radiotherapy directed at the primary tumor (NCT01957436) (Figure 11).
  2. The STAMPEDE trial continues adding treatment arms including arm J which combines abiraterone with enzalutamide,47 arm K investigating  ADT + metformin,48 and arm L assessing transdermal oestradiol49 (Figure 12)
  3. Darolutamide is a novel anti-androgen, structurally distinct from Enzalutamide and has a higher affinity for the AR than Enzalutamide or Apalutamide.50 A phase I/II study of Darolutamide in men with metastatic CRPC (ARADES) showed that it had adequate safety and toxicity profiles.51 In 2019 a published prospective randomized phase 3 trial (ARAMIS) showed that men with non-metastatic CRPC treated with Darolutamide had a median metastasis-free survival of 40.4 months compared to 18.4 months with placebo (HR for metastasis or death in the Darolutamide group 0.41, 95% CI 0.34-0.50, P<0.001).52 Darolutamide also demonstrated substantial benefits in all secondary endpoints, including OS, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic SRE event.52 The ARASENS trial is randomizing 1300 men with mHSPC receiving ADT plus docetaxel with or without Darolutamide (NCT02799602), and the results are anticipated in 2022.
  4. Orteronel (TAK-700) is a novel, reversible CYP17 inhibitor with more specificity for 17,20 lyase than Abiraterone. Orteronel has been previously shown to inhibit testosterone and dehydroepiandrosterone sulfate production and reduce PSA levels in metastatic CRPC patients.53 A phase II study in nonmetastatic CRPC patients showed that Orteronel resulted in a PSA reduction of more than 30%.54 There is currently an ongoing SWOG 1216 trial, which is a phase III clinical trial that has completed randomization of 1304 mHSPC mento ADT and Orteronel or bicalutamide, with the primary endpoint of OS.
  5. A study assessing the role ofRucaparib, a poly ADP ribose polymerase (PARP) inhibitor in patients harboring germline DNA repair gene mutations, the (TRIUMPH) trial (NCT03413995).
  6. There are also studies assessing the role of immunotherapy in the mHSPC setting, including the role of Ipilimumab and an LHRH antagonist (Degarelix) (NCT02020070), the combination of docetaxel with Ipilimumab and Nivolumab (NCT03879122), and the combination of docetaxel with the PROSTVAC vaccine (NCT02649855) and (NCT03532217).
  7. A phase 2 study is assessing the role of Cemiplimab (REGN-2810), a monoclonal antibody, in mHSPC (NCT03951831).
figure-10-PEACE-1-trial2x.jpg
figure-11-STAMPEDE2x.jpg

Conclusions


There have been a plethora of studies in the last few years manifesting the advances made in the mHSPC space. Combination systemic therapies, including chemotherapy with ADT and Abiraterone with ADT, have been declared as the standard of care for mHSPC. Aside from the novel treatments constantly being added, there is a clear trend of using our armamentarium in earlier stages of the disease. 

This is a rapidly changing and dynamic field, and in the next few years, more treatment options will become available in an attempt to improve disease outcomes and patients’ quality of life. With this growing assortment of treatment options, our next major challenge is to strategize and properly allocate each of the available medications or their combinations to the right patients to obtain a maximal benefit.

Published Date: February 1st, 2020
Written by: Hanan Goldberg MD, Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
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