Most men with de novo mHSPC will not receive primary surgery; the histologic diagnosis is typically performed on a prostatic biopsy. Therefore, a liquid biopsy could add clinically relevant information in this setting. In a single-center prospective cohort, Vanderkerhove et al.
detected a median plasma ctDNA fraction of 11% (range 2.0–84%) among 26 out of 35 (74%) untreated patients with de novo mHSPC; for the remaining 9 patients, ctDNA was not detectable. Higher ctDNA levels were identified in the presence of visceral metastasis. A somatic analysis of ctDNA and tumor tissue revealed a mutational landscape like mCRPC, although without
and DDR gene mutations were identified in 47% and 21% of the cases, respectively. The rate of concordance for mutation detection between tumor tissue and ctDNA was 80%, suggesting that de novo mHSPC was a highly clonal disease at diagnosis. On the other hand, in a cohort of 82 Chinese patients with de novo mHSPC, only 50% of men had a ctDNA fraction >2% and the percentage of ctDNA-positive patients was even lower (37%) in a cohort of 73 untreated mHSPC, including both de novo and metachronous disease
.
From a prognostic point of view, data regarding the association between the genetic alterations, time to castration resistance, and OS for de novo mHSPC are partial because they were obtained from cohorts including both synchronous and metachronous metastatic disease. Among 424 cases of mHSPC, including 275 men with de novo mHSPC, Stopsack et al.
[39] reported a rate of progression to castration resistance that was 1.6-to-5-fold higher in the presence of alterations in
AR,
TP53, cell cycle, and MYC pathways and approximately 1.5-fold lower with
SPOP and Wnt pathway alterations; similarly, the OS rate was 2-to-4-fold higher in the presence of
AR or cell cycle alterations, and 2-to-3-fold lower if the
SPOP or Wnt pathway was altered. The sequencing of FFPE tissue from biopsies of 43 patients affected by mHSPC, of whom 30 had de novo disease, revealed a slightly poorer OS with cumulative mutations or alterations in the tumor suppressor genes
TP53,
PTEN, and
RB1 [40]; the negative prognostic value of alterations in
TP53,
PTEN, and
RB1 was also observed in a cohort of 97 men with mHSPC treated with first-line ADT plus docetaxel or abiraterone acetate, outperforming clinical criteria that predict early disease progression
[41]. An association between a shorter OS and alterations in
TP53,
ATM, and DDR genes detected on plasma ctDNA was also observed among 53 patients with de novo or metachronous untreated mHSPC
[38].
4. Ongoing Phase III Clinical Trials Testing New Therapeutic Approaches for mHSPC
4.1. Immunotherapy
Although the expression of programmed death ligands 1 and 2 (PD-L1 and PD-L2) on PC cells is highly variable, therapy with enzalutamide can upregulate PD-L1 expression in the tumor microenvironment; this can represent a mechanism of resistance by inducing immune evasion
[42]. In the phase Ib Keynote-028 and phase II Keynote-199 trials, mCRPC enzalutamide-refractory patients and previously untreated patients received a combination of pembrolizumab and enzalutamide, reaching potentially improved and durable response rates
[43][44]. Based on these premises, the ongoing randomized, double-blind, placebo-controlled phase III KEYNOTE-991 (NCT04191096)
[45] is investigating whether this combination therapy for NHA-naive patients with mHSPC is superior to enzalutamide plus placebo. Stratification by prior docetaxel therapy and the presence of high-volume mHSPC is planned. Pembrolizumab 200 mg every three weeks will be administered for up to 35 cycles, loss of clinical benefit, or intolerable AEs. The two co-primary endpoints are the OS and rPFS. Archival or newly obtained tumor tissue and blood for genetic, RNA, serum, and plasma biomarkers and ctDNA analyses will be collected from all participants to support exploratory analyses of novel biomarkers. PROSTRATEGY (NCT03879122) is another phase III clinical trial that is investigating the role of immunotherapy for high-volume mHSPC
[46].
4.2. Radiopharmaceuticals
Lutetium-177(177Lu)-PSMA-617 is a beta emitter radioisotopic agent that was approved by the FDA in 2022 for the treatment of mCRPC in men who had progressed to an NHA and taxane-based chemotherapy, and whose metastatic lesions express the prostatic-specific membrane antigen (PSMA), as documented via PSMA imaging
[47]. Radiopharmaceuticals release alpha or beta radiation to cancer cells via radioisotopes; radiation activates apoptosis via single- and double-strand DNA breaks
[48]. PSMAddition (NCT04720157)
[49] is a phase III, randomized, open-label, international, prospective clinical trial that aims to evaluate the efficacy and safety of 177Lu-PSMA-617 in combination with the SOC (ADT plus NHA) versus SOC alone for mHSPC. About 1126 patients will be randomized 1:1 to receive the SOC, with or without 177Lu-PSMA-617 administered once every 6 weeks for six cycles. The exclusion criterion will be a rapidly progressing tumor that requires chemotherapy. The primary endpoint will be the rPFS. Stratification according to age (≥70 years/<70 years), high-volume vs. low-volume disease, and prior/planned prostatectomy or radiotherapy of the prostate is planned.
4.3. Molecular Target Agents
4.3.1. CDK4/6 Inhibitors
During the G1-S checkpoint, CDK4/6 activation by the AR axis contributes to cancer cell proliferation; among the mechanisms of resistance to NHA, the upregulation of cyclin D1 (whose association with CDK4/6 is crucial for the transition from G1 to S phase) was described
[50]. CYCLONE-03 (NCT05288166)
[51] is a placebo-controlled phase III study that will randomize about 900 patients affected by high-risk NHA-naïve mHSPC (defined by at least four bone metastasis and/or visceral disease) to receive either abemaciclib (a selective CDK4/6 inhibitor) or a placebo, plus abiraterone and prednisone. Visceral metastases and de novo mHSPC will be the stratification factors. The primary endpoint will be the rPFS.
4.3.2. PARP Inhibitors
Preclinical and clinical evidence showed that the co-inhibition of the AR axis and PARP generates a combined anti-tumor effect: PARP is involved in the positive co-regulation of AR signaling, and thus, PARP/AR signaling co-inhibition leads to enhanced AR target gene suppression; moreover, treatment with NHAs inhibits the transcription of some DDR genes, inducing synthetic lethality due to cancer cells’ inability to repair DNA, even in patients without any DDR alterations
[52]. The combination of the PARPi olaparib with abiraterone is FDA- and EMA-approved as a first-line treatment of mCRPC if chemotherapy is not clinically indicated, according to the results of PROPEL
[53]. The combination of the PARPis talazoparib and enzalutamide was recently FDA-approved as a first-line treatment for men with homologous recombination repair (HRR) gene-mutated mCRPC, according to TALAPRO-2
[54]. The association of the PARPi niraparib with abiraterone was evaluated both in patients with and without HRR gene-altered mCRPC in the phase III MAGNITUDE trial
[55]. Differently from PROPEL, the superiority of the experimental treatment over the control arm (abiraterone plus placebo) was demonstrated only in the cohort with HHR gene-altered mCRPC, while in the HRR proficient cohort, futility was confirmed per the prespecified criteria.
4.3.3. AKT Inhibitors
Inactivation of the tumor suppressor gene
PTEN via deletion or mutation is frequent in PC, especially in late-stage tumors. PTEN loss of function determines PI3K/AKT signaling pathway activation and suppression of AR transcriptional output. AKTi activates AR signaling, suggesting the potential efficacy of the inhibition of both PI3K and AR signaling pathways
[56]. Evidence supporting this association came from the phase III trial IPATential150
[57], which demonstrated that the AKTi ipatasertib, in association with abiraterone, improved the rPFS in patients with mCRPC and PTEN-loss. CAPItello-281 (NCT04493853)
[58], which is a randomized double-blind trial, will test the AKTi capivasertib. Approximately 1000 patients with PTEN-deficient mHSPC, as demonstrated using tissue immunohistochemistry (IHC), will be randomized 1:1 to receive capivasertib or a placebo in association with abiraterone. The primary endpoint will be the rPFS.
5. Conclusions
The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. Transcriptomic profiling of mHSPC revealed a predominance of aggressive and poor prognosis subtypes, but its role as a predictive biomarker requires further validation. Even though many of the genomic alterations detected in mHSPC are regarded as predictive in mCRPC, it remains to be ascertained how these alterations can be exploited in the mHSPC setting. In this sense, the ProBio (NCT03903835) trial, which is randomizing both mHSPC and mCRPC to receive SOC following national guidelines (control arm) or therapies based on a biomarker signature obtained from diagnostic tissue or liquid biopsy profiling (experimental arm), will probably provide a prospective evaluation of biomarker-driven treatments.