Metastatic hormone-sensitive prostate cancer: the three-drug regimen is expected to set the new standard

Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists has been the standard of care
for patients with metastatic hormone-sensitive prostate cancer (mHSPC) for decades.
Although the initial response rate is high, most patients inevitably develop castration-resistant prostate cancer
within 1~3 years.
Since then, various dual-agent treatment strategies such as ADT combined with antiandrogen therapy, combination chemotherapy, and combination molecular targeted therapy have been explored, and the results show that these combination regimens significantly improve the prognosis
of mHSPC.
At present, ADT in combination with chemotherapy or androgen receptor (AR) pathway inhibitors is gradually becoming the standard of care
for patients with mHSPC.

In recent years, the effect of
three-drug combination therapy has been further studied on this basis.
Although subgroup analyses of the ARCHES, ENZAMET, and TITAN trials did not demonstrate that three-drug intensive therapy prolongs overall survival, the PEACE-1 trial confirmed that abiraterone + ADT + docetaxel significantly prolongs overall survival in mHSPC
.

In March 2022, the New England Journal of Medicine (NEJM) published the results of the ARASENS trial, confirming that the new AR pathway inhibitor darolutamide combined with ADT and docetaxel in the treatment of mHSCP can significantly improve overall survival and the risk of adverse events is not increased
.
The results of this study are expected to promote the standard treatment regimen of mHSPC from two-drug combination to three-drug intensive therapy
.

As one of the main investigators of the ARASENS trial in China, Professor Ye Dingwei of Fudan University Cancer Hospital comprehensively reviewed the research progress and future direction
of the three-drug combination therapy for mHSPC.
In particular, Prof.
Ye "looks forward to more relevant studies in China in the future to enrich the evidence-based medical evidence of the three-drug combination regimen in the treatment of prostate cancer"
.
           

Ye Dingwei

Fudan University Cancer Hospital

In recent years, many important progress has been made in the field of prostate cancer treatment, and the standard treatment regimen for metastatic hormone-sensitive prostate cancer (mHSPC) has been changed from monotherapy to androgen deprivation therapy (ADT) + chemotherapy/new endocrine drug combination therapy [1], but most patients still develop castration-resistant prostate cancer within 1~3 years, and the prognosis is poor
。 SUBGROUP ANALYSES OF PREVIOUS ARCHES, ENZAMET, AND TITAN STUDIES SUGGEST THAT ADT IN COMBINATION WITH A SECOND-GENERATION ANDROGEN RECEPTOR ANTAGONIST (ENZALUTAMIDE OR APATAMIDE) DOES NOT CONFER AN OVERALL SURVIVAL (OS) BENEFIT IN PATIENTS PREVIOUSLY TREATED WITH DOCETAXEL [2-4].

Therefore, more evidence-based medical evidence
is needed for the optimal treatment of chemotherapy, ADT, and novel endocrine drugs in patients with mHSPC.
The results of two triple therapies published this year, including the PEACE-1 and ARASENS studies, published in Lancet and the New England Journal of Medicine (NEJM), respectively, are a powerful illustration of the benefits of early intensification for patients, ushering in a new era
of mHSPC triple therapy.

PEACE-1 is a multicenter, open-label, randomized, 2x2 factorial-designed phase 3 trial [5] that enrolled 1173 patients with new-onset mHSPC who were randomized to receive standard care (ADT or ADT plus docetaxel), standard care plus and local radiotherapy, standard care plus and abiraterone
, standard care plus local radiotherapy and abiraterone 。 The results showed that the three-drug combination regimen only benefited from ADT plus docetaxel in patients with high tumor burden (radiographically progression-free survival: 4.
1 years vs.
1.
6 years; HR, 0.
47;99.
9% CI,0.
30~0.
72;P<0.
0001;OS:5.
1 years vs.
3.
5 years; HR，0.
72；95.
1% CI，0.
55~0.
95；P=0.
019）； In patients with low tumor burden, the three-drug combination regimen did not have a significant benefit
compared with standard treatment of OS.

In terms of safety, the addition of abiraterone to ADT plus docetaxel was associated with an increased
incidence of ≥grade 3 hepatotoxicity (6% vs.
1%) and hypertension (22% vs.
13%).
Given the increased risk of ≥ grade 3 hepatotoxicity and hypertension with the addition of abiraterone, the risk-benefit profile of this three-drug combination regimen requires further study
.

ARASENS is the world's first randomized, double-blind, placebo-controlled phase 3 trial that directly compares a three-drug combination regimen with a two-drug regimen [6], enrolling a total of 1306 new or relapsed mHSPC patients (including more than 200 Chinese patients) who received oral AR inhibitor darolutamide 600 mg or placebo (twice daily) in a 1:1 ratio, and both groups received standard care (ADT + docetaxel).

。 Results found that darolutamide + standard care significantly reduced the risk of death by 32.
5% compared with placebo + standard care (median OS: unestimateable vs.
48.
9 months; HR，0.
68；95% CI，0.
57~0.
80；P<0.
001）； Patients in the darolutamide group had delayed
development of castration-resistant prostate cancer, time to pain progression, and need for other anticancer therapies.
In terms of safety, adverse events were similar
in the darolutamide or placebo groups (38.
0% vs.
35.
7%), grade 4 (28.
1% vs.
27.
8%), and grade 5 (4.
1% vs.
4.
0%).

At the American Clinical Oncology (ASCO) 2022 Annual Meeting, investigators reported the latest results of ARASENS, showing that darolutamide significantly extended the progression time to PSA (HR, 0.
26; 95% CI, 0.
21~0.
31; P<0.
0001), and the proportion of patients with PSA not detected at any time in the darolutamide group (67.
3%) was more than
twice that of patients in the placebo group (28.
6%) 。 At the 2022 Annual Meeting of the European Academy of Urology (EAU), investigators reported the results of a preset subgroup analysis of the ARASENS trial, showing a trend of benefit for OS in the darolutamide group (49.
0 months vs.
42.
0 months; HR，0.
76；95% CI，0.
53~1.
10）
。

Eleven studies were included in a recent meta-analysis to compare the efficacy of two- and three-drug combinations [7].

The results showed that docetaxel + ADT+ARAT reduced the risk of death by 11% compared with ADT+ androgen receptor axis-targeted therapy (ARAT, including androgen synthesis inhibitors and second-generation androgen receptor antagonists), but the difference was not statistically significant (HR, 0.
89; 95% CI, 0.
68~1.
16).

。 In order of P value, the three-drug combination regimen was the most effective treatment strategy (P score=0.
936), followed by ADT+ARAT (P score=0.
704).
The probability that the three-drug combination regimen is the optimal treatment strategy is 77%, compared with the probability of ADT+ARAT dual-agent regimen is 23%.

The results of the above studies comprehensively show that the three-drug combination strategy is superior to the standard therapy of two-drug combination therapy
.
Given the efficacy and safety data available for three-drug combinations (Table 1), darolutamide-based three-drug combination therapy may be the most promising therapy
for the treatment of mHSPC at present.

Table 1 Analysis of efficacy and safety of related studies of three-drug combination therapy

*Clinical PFS; #PFS

Patients who have failed prior novel endocrine therapy and have not received chemotherapy can be treated sequentially with docetaxel second-line therapy, but an early combination of novel endocrine therapy and docetaxel with intensive therapy may increase patient benefit
.
The PEACE-1 study showed that the median OS of patients with standard therapy (ADT alone or ADT + docetaxel) combined with new endocrine first-line therapy was 5.
7 years, while the median OS of patients receiving ADT + novel endocrine + docetaxel tridrug combination did not reach [5].

Meta-analysis showed that docetaxel+ADT+ARAT was superior to ADT plus ARAT (P score=0.
936 vs.
P score=0.
704) [7].

。 Despite the lack of parallel controlled clinical trials with sequential and combination strategies, given that early use of docetaxel can delay the emergence of castration resistance in patients with high tumor burden [8], and that there are still multiple treatment options (eg, abiraterone, cabataxel, enzalutamide, radium-223, etc.
) after progression of three-drug combination therapy, first-line therapy may have more clinical benefits
than ADT+ novel endocrine therapy.

In terms of safety, chemotherapy drugs are well tolerated in treatment-naïve patients [9], and the early use of three drugs is conducive to prolonging the medication time and giving full play to the efficacy
of drugs.
The ARASENS study showed that no significant increase in grade 3 or higher adverse events was observed with the combination of three drugs, and adverse events occurred similarly in both groups [6].

Based on the comprehensive efficacy and safety data, ADT+ docetaxel + daroltamine may be the best choice
.

Of course, research on three-drug combination therapy also has certain limitations
.
PEACE-1 included patients with newly diagnosed mHSPC with a performance status score of 0~2 in the Eastern Cooperative Oncology Group (ECOG), and it is unclear whether this triple therapy is beneficial
in patients with metachronous mHSPC.
Because the study design did not focus on the efficacy of chemotherapy, the triad regimen could only be compared in post-hoc analysis for the superiority of ADT plus abiraterone, and the evidence was low
.
The patients included in the ARASENS study were mHSPC and ECOG performance status scores were all 0~1 points, so it was not possible to evaluate the effect
of the darotamide triple regimen on the prognosis of patients with poor performance status.

Recent research progress in the three-drug combination regimen has established a new regimen with significantly better survival outcomes than standard therapy, which is of great significance for improving the prognosis of patients with mHSPC, suggesting that the three-drug combination may be a better choice
for patients with mHSPC.
However, among the many three-drug combination regimens, only darolutamide
is the newer endocrine drug that has been shown to be superior to both drugs in large randomized controlled trials.
Darolutamide is a novel non-steroidal AR inhibitor with high affinity for AR, low affinity with neurotransmitter γ-aminobutyric acid receptor, low blood-brain barrier transmittance, low impact on metabolic enzymes in vivo, and low possibility of drug interaction, and the efficacy and safety
of darolutamide have been confirmed in the currently approved non-metastatic castration-resistant prostate cancer indications and real-world drugs 。 According to the principle of "hit hard, hit early", the combination of durostatamide on the basis of ADT + chemotherapy provides a new idea of mHSPC treatment, which will bring more options to clinical practice and is expected to replace ADT two-drug combination therapy and become a new standard treatment regimen
.

Nevertheless, it is necessary to continue to explore the optimal population for the treatment of mHSPC with the darotamide triple regimen and the benefits of ECOG patients with poor performance status, so as to provide a basis for
precision therapy.
In addition, there are a variety of treatment options for patients who develop disease progression after three-drug combinations, but there is a lack of high-quality evidence on the optimal follow-up regimen and further research
is needed.
It is expected that more relevant studies will emerge in China in the future to enrich the evidence-based medical evidence
of the three-drug combination regimen in the treatment of prostate cancer.

(This article only represents the views of experts, not the views of NEJM Medical Frontiers)

References