Newly presenting or de novo metastatic hormone-sensitive prostate cancer (mHSPC) accounts for 5% to 10% of all prostate cancer (PC) diagnoses, but it is responsible for nearly 50% of PC-related deaths.¹ De novo mHSPC is characterized by an aggressive course with faster development of castration resistance and worse overall survival (OS) in contrast with metachronous mHSPC presenting after failed local therapy.² Notably, the incidence of de novo mHSPC is increasing in the US, in part due to the reduction in PSA opportunistic screening and more recently the introduction of new diagnostic tools in the imaging of PC, such as PSMA-PET (prostate-specific membrane antigen–positron emission tomography). Analysis of SEER (Surveillance, Epidemiology, and End Results) datasets indicate that during the past 5-year period (2015-2019), incidence rates for regional- and distant-stage disease increased by 4% to 6% per year for all racial and ethnic groups.^3,4 However, the prognosis of mHSPC has improved due to the introduction of new hormonal agents and chemotherapy, combined with standard androgen deprivation therapy (ADT) in the first-line setting. In some scenarios, improved control of the primary tumor with radiation improves outcomes. Promising approaches using molecular biomarker-guided treatment in place of current parameters based on clinical features (eg, high-volume vs low-volume disease, visceral vs bone-only metastasis) will alter the approach we employ in de novo disease moving forward.

ADT Alone Is No Longer the Standard of Care for mHSPC

Advanced PC guidelines recommend the use of combination therapy rather than ADT alone for patients with mHSPC.⁵ The paradigm shifting phase 3 CHAARTED trial randomized 790 patients affected by mHSPC (73% of them with de novo disease), with the aim to verify the superiority of upfront docetaxel for 6 cycles in association with ADT vs ADT alone. In patients with high-volume disease (≥4 bone metastatic lesions with 1 or more beyond the axial skeleton and/or using evidence of visceral metastases by conventional imaging), OS of 16.8 months was observed in the experimental arm compared with ADT alone (median OS: 51.2 vs 34.4 months, HR: 0.63, 95% CI: 0.50-0.79, P < .001). No benefit was reported in low-volume mHSPC. This chemohormonal therapy approach was validated in several additional phase 3 trials including STAMPEDE and GETUG-AFU15.⁵

Many elderly patients may not be candidates for chemotherapy, and subsequent phase 3 trials extended this combination approach by employing oral androgen signaling inhibitors (ASI) including ADT plus abiraterone (LATITUDE trial), enzalutamide (ARCHES and ENZAMET), and apalutamide (TITAN trial).⁵ These oral agents can be employed in the urologist’s office but require knowledge of side effects and indications.

Triplet Therapy for High-Risk mHSPC

More recently, the need for treatment intensification was expanded by employing so-called “triplet therapy” in patients with high-risk mHSPC. In the phase 3 ARASENS trial, 1306 patients were randomized to either darolutamide or placebo in addition to docetaxel for 6 cycles and ADT.⁶ A reduction in risk of death in the daralutamide group vs placebo (HR: 0.68, 95% CI: 0.57-0.80, P < .001) was seen at a median follow-up of 43.7 months. Adverse events were similar in both arms with the most common being grade 3 or 4 neutropenia associated with docetaxel. PEACE-1 enrolled 1173 patients with de novo mHSPC to a more complex 2 × 2 factorial design trial. Patients were randomized to ADT plus docetaxel as standard of care (SOC), SOC plus external beam therapy, SOC plus abiraterone, or SOC plus abiraterone and external beam radiation therapy (EBRT) to the primary tumor.⁷ A significant benefit in terms of the median OS was noted for patients receiving abiraterone (5.72 vs 4.72 years, HR: 0.82, 95% CI: 0.69-0.98, P = .03), with a risk of death from any cause being 18% lower than in those who did not receive it. Toxicity with oral abiraterone included primarily hypertension and elevated liver aminotransferase enzymes.

Both ARASENS and PEACE-1 show that upfront treatment intensification with the combination of ADT, docetaxel, and an ASI for de novo mHSPC improved survival outcomes with an acceptable safety profile (Figure). This is especially pertinent in patients with high-volume symptomatic disease without severe comorbidities. However, in elderly patients with cognitive issues or fatigue, the ASIs enzalutamide and apalutamide are potent inducers of CYP3A4 and may increase the risk of mental impairment.

Figure. Current options for de novo metastatic hormone-sensitive prostate cancer according to metastatic burden. Options are not exclusive or in order of preference. ADT indicates androgen deprivation therapy; EBRT, external beam radiation therapy; MDT, metastasis-directed therapy; pred, prednisone. *EBRT to sites of bone metastases can be considered if metastases are in weight-bearing bones or if the patient is symptomatic.

In Oligometastatic Disease Control of the Primary Improves OS

Oligometastatic disease encompasses a diverse group of tumors characterized by a lower metastatic burden as defined by the CHAARTED criteria or alternatively 3 to 5 metastatic lesions. De novo oligometastatic disease has a better survival than higher-volume cancer and does not appear to benefit from chemohormonal therapy. In this minimal disease population, several studies have demonstrated that improving locoregional control, primarily with radiation, leads to improved survival. These definitions may change however given the increased sensitivity of PSMA-PET–based imaging.

In the HORRAD trial, mHSPCs were randomized to receive only ADT or ADT in combination with EBRT to the primary tumor.⁸ A subgroup analysis demonstrated a trend toward an OS benefit in men with fewer than 5 skeletal lesions (HR: 0.68, 95% CI: 0.42-1.10). These promising results were examined in the STAMPEDE trial (arm H) and EBRT to the prostate increased the 3-year survival rate from 73% to 81% that received EBRT.⁹ In a recent phase 2 trial including 200 men with de novo oligometastatic metastatic prostate cancer (mPC) randomized to receive either ADT or ADT plus radical local treatment on the prostate, both the radiographic progression-free survival and OS were significantly improved with radiation.¹⁰ This improvement may be due, in part, to decreased tumor cell dissemination from the primary cancer in patients who have a longer survival in the modern era with mPC. Therefore, EBRT to the prostate in association with systemic treatment is recommended for men with low-volume mHSPC according to the AUA and European Society for Medical Oncology guidelines.

New Approaches for Patients With De Novo mHSPC

Personalized approaches to therapy using the molecular makeup of the tumor have begun to alter the management of metastatic PC. Alterations in homologous recombination repair genes, including BRCA1/2, are found in approximately one-quarter of patients with advanced PC and can sensitize patients to treatment with Poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors trap PARP on single-strand DNA breaks, preventing DNA repair leading to cancer cell death. In castration-resistant mPC, the PARP inhibitors talazaparib combined with enzalutamide (TALAPRO-2)¹¹ or olaparib and abiraterone (PROPEL)¹² improve OS in patients with homologous recombination repair mutations. PARP inhibition and ASIs in de novo mHSPC are being currently tested in the TALAPRO-3 and AMPLITUDE trials. In another approach, patients with phosphatase and TENsin homolog–deficient mHSPC are being targeted with a selective Ak strain–transforming inhibitor or placebo in association with abiraterone in the ongoing phase 3 CAPItello281 trial.

Other phase 3 trials will test a selective CDK4/6 inhibitor in combination with abiraterone in high-risk mHSPC patients (CYCLONE-03). Finally, the novel theranostic Lutetium-177, a β emitter radioisotopic agent approved by the Food and Drug Administration for PSMA-expressing mCRPC,¹³ will be tested in combination with the SOC (ADT plus ASI) vs SOC alone for mHSPC.

Thus, the urologic community has a number of new options for the treatment of de novo mHSPC. ADT alone is no longer the treatment of choice. Promising biomarkers associated with our clinical interventions highlight the potential importance of germline and somatic testing in patients with advanced mPC.