Triplet therapy for metastatic castration-sensitive prostate cancer: Rationale and clinical evidence

Abstract

Prostate cancer (PC) growth is hormone-dependent and it frequently develops distant metastases as disease progresses. Patients with metastatic castration-sensitive prostate cancer (mCSPC) initially respond to androgen deprivation therapy (ADT) but eventually become refractory and develop metastatic castration-resistant prostate cancer (mCRPC). Castration-resistance is associated with high lethality and metastases confer poor prognosis, therefore unmet needs in treatment for mCSPC remain high. So far, improvements in survival in mCSPC have been achieved by doublet combination therapy such as docetaxel or an androgen-receptor signaling inhibitor (ARSI) in addition to ADT. Further, recent phase 3 trials have shown that triplet therapy-a combination of ARSI, docetaxel, and ADT improves prognosis compared with docetaxel plus ADT in mCSPC. PC tumors manifest intra- and inter-tumoral heterogeneity at both the genetic and phenotypic level. As heterogeneity increases during sequential treatment and disease progression, it is reasonable to initiate combination therapy using drugs with different mechanisms of action early in the course of disease, such as mCSPC. Previous research about tumor heterogeneity and drug resistant mechanism support this rationale, as well as preclinical studies and real-world data provide the scientific evidence of benefit by combining ARSI and docetaxel. Here, we review the rationale and clinical evidence for triplet therapy in patients with mCSPC.

Keywords: androgen receptor signaling inhibitor; docetaxel; metastatic castration‐sensitive prostate cancer; prostate cancer; triplet therapy.

FIGURE 1

Heterogeneity of prostate cancer. (a) Tumor heterogeneity includes intratumoral heterogeneity, intertumoral heterogeneity, and metachronous heterogeneity (lineage plasticity). (b) Tumor heterogeneity increases during sequential treatment and disease progression. Clones have the potential for continued proliferation and a selective growth advantage (Darwinian selection); therefore, tumors can evolve by the expansion of one (monoclonal) or multiple (polyclonal) subpopulations to form the tumor mass. According to the later model “Darwinian selection”, genetic instability induced by disease progression or treatment pressure creates new clones (i.e., sub clone). In this manner, tumors evolve with increased heterogeneity during disease progression and sequential treatment. (c) The mechanism of drug resistance. In the Adaptation model, androgen‐dependent prostate cancer cells (blue) acquire (epi)genetic program to allow androgen‐independent growth under suppression of androgen, and the resistant cells (orange) proliferate. In the Clonal selection model, heterogenous prostate cancer cells, including androgen‐independent cells (green), coexist from an early stage of disease or at the treatment‐naïve stage. ADT/treatment induces selective sweep, causing extinction of sensitive cancer cells, and outgrowth of pre‐existing resistant cells. ADT, androgen deprivation therapy.

FIGURE 2

Pre‐clinical evidence for the rationale of combining ARSI and taxane anticancer drugs. (a) ARSI and docetaxel have different advantages. Real‐world studies suggest that the efficacy of taxanes is greater than that of ARSI in patients with AR amplification, PTEN aberrations or RB1 aberrations, while the efficacy of ARSI is better than taxanes in patients with SPOP mutations. (b) While the primary mode of action of docetaxel is stabilization of microtubules, which results in the inhibition of mitosis in cells, docetaxel also has an action against the AR, in which it inhibits nuclear translocation of AR. Also, MRP4 is known to be involved in one of the mechanisms of docetaxel resistance. MRP4 expression is regulated by AR signaling, being upregulated by androgen. Because MRP4 expression is downregulated by ARSI, it can lead to the reduction of extracellular efflux of docetaxel, which results in restoring the cytotoxicity effect of docetaxel. (c) ARSI‐resistant cells show collateral resistance to taxanes; therefore, if docetaxel is administered sequentially after ARSI, efficacy might not be optimal. In addition, activation of AR signaling affects taxane‐sensitivity in prostate cancer cells; therefore, ARSI administration concurrently combined with docetaxel can augment the cytotoxic effect of docetaxel. These findings support the idea that the upfront use of taxanes in combination with ARSI is reasonable, rather than sequential treatment. AR, androgen receptor; ARSI, androgen‐receptor signaling inhibitor; DHT, dihydrotestosterone; MRP4, multidrug resistance protein 4.