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Androgen receptor signaling inhibitors in addition to docetaxel with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis

  • Takafumi Yanagisawa,
  • Pawel Rajwa,
  • Constance Thibault,
  • Giorgio Gandaglia,
  • Keiichiro Mori,
  • Tatsushi Kawada,
  • Wataru Fukuokaya,
  • Sung Ryul Shim,
  • Hadi Mostafaei,
  • Reza Sari Motlagh,
  • Fahad Quhal,
  • Ekaterina Laukhtina,
  • Maximilian Pallauf,
  • Benjamin Pradere,
  • Takahiro Kimura,
  • Shin Egawa,
  • Shahrokh F. Shariat

Context

Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Objective

To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.

Evidence acquisition

Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.

Evidence synthesis

Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65–0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42–0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55–0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51–0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53–0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.

Conclusions

We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.

Expert's summary

By Dr. Constance Thibault

The management of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has widely changed since 2015. Several trials have shown an overall survival benefit adding new hormonal therapy (LATITUDE, STAMPEDE, TITAN, ENZAMET, ARCHES) or docetaxel (CHAARTED study, STAMPEDE) to androgen deprivation therapy (1-7). More recently, two phase III trials compared a triplet regimen based on docetaxel + ADT + new hormonal therapy (NHT) (respectively darolutamide and abiraterone in ARASENS and PEACE-1 trials) to a doublet regimen ADT + docetaxel. Both studies reported an overall survival benefit in favour of the triplet therapy. However, there are no head-to-head comparisons regarding triplet therapy versus doublet therapy combining ADT + NHT. Yanagisawa et al. have therefore conducted a systemic review, a meta-analysis and a network meta-analysis to compare the efficacy of the doublet with NHT, the doublet with docetaxel and the triplet with docetaxel and NHT.

They selected 11 randomised controlled trials comprising 7.679 patients eligible for meta-analysis and network meta-analysis (PEACE-1, ARASENS, LATITUDE, ENZAMET, ARCHES, TITAN, GETUG-15, CHAARTED and three studies from STAMPEDE platform). A benefit in terms of PFS and OS was observed in favour of the triplet therapy in the five studies that compared the triplet vs the doublet ADT + docetaxel (n=2.837).

The timing of docetaxel administration (concomitant with ADT + NHT or sequentially before NHT) didn’t impact the results. Based on network meta-analysis, the triplet therapy had the higher likelihood of proving the maximal OS benefit, especially in de novo mHSPC and in high-volume mHSPC. In contrast, it was the doublet ADT + new hormonal therapy for metachronous mHSPC and low volume mHSPC. Moreover, the triplet statistically reduced the risk of death when compared to doublet based on ADT + new hormonal therapy (HR: 0.74, 95% CI: 0.55–0.99). However, the triplet had also the higher likelihood of any and severe AEs. 

Expert's comment

This work confirms the results of subgroups analyses of PEACE-1 and ARASENS which suggested the patients who benefit most from the triplet therapy are de novo and high-volume mHSPC. But this is the first time that a meta-analysis reports a better OS with triplet therapy compared to a doublet based on ADT + new hormonal therapy.

However, these results must be interpreted with caution. Indeed, even though a meta-analysis provides interesting results, it’s less robust than a head-to-head comparison in a phase III trial. Moreover, another recent meta-analysis reported conflicting results with no statistically significant benefit adding docetaxel to a doublet ADT +new hormonal therapy (8). These results highlight that the triplet therapy should be the preferred option for patients with de novo and high volume mHSPC if the patient is eligible for docetaxel. But there is still doubt about the best treatment in patients with metachronous and low volume mHSPC patients: triplet or doublet with ADT + new hormonal therapy?

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