Future Directions in Systemic Treatment of Metastatic Hormone-Sensitive Prostate Cancer

The treatment of metastatic prostate cancer has seen a paradigm shift, particularly in the management of metastatic hormone sensitive prostate cancer (mHSPC). The developments come not only on the fronts of systemic agents but also in the area of therapy to primary tumour and metastases. The consistent survival benefit seen in landmark trials of androgen receptor inhibitors (ARIs) have collectively put forth a strong argument for early intensification of treatment. Together with level 1 evidence from CHAARTED and STAMPEDE, docetaxel or ARIs in combination with ADT are now established as the new standard of care for de novo mHSPC.

More recently, the ARASENS and PEACE trials have taken the concept of treatment intensification further by demonstrating survival benefits from the combination of chemotherapy (docetaxel) and ARIs (abiraterone and darolutamide) in addition to backbone therapy of ADT. This has heralded the strategy of triplet therapy although the most significant benefit will likely be derived from patients with high metastatic burden as shown by PEACE-1. Intensification of treatment has also seen evidence supporting local therapy to the primary tumour with OS and biochemical recurrence-free survival although only evident in low volume synchronous metastases. There is emerging evidence for metastases-directed therapy as well with pooled data suggesting improved biochemical-free (HR: 0.44, 95%CI 0.29 – 0.67, p<0.01) and ADT-free survival (HR: 0.56, 95%CI 0.34 – 0.94, p=0.03).

Although robust clinical data has demonstrated survival benefits with upfront treatment intensification, several challenges remain in the management of mHSPC. Subgroup analysis has alluded to the importance of tailoring treatment according to metastatic disease burden. However, the advent of next generation imaging such as PSMA PET challenges our traditional definitions of disease burden. Beyond the Will Roger’s phenomenon, PSMA PET results in a key clinical dilemma with regards to the optimal management of patients with localised disease on conventional imaging but PSMA-evident metastatic disease. As the treatment milieu of mHSPC expands beyond chemohormonal options, with ongoing trials (see Table informing the role of new agents such as PARPi, checkpoint inhibitors, and radioligand therapy in the coming years, it is equally important to sharpen the selection criteria of patients who will benefit most. Several emerging biomarkers are under evaluation in mHSPC to aid in risk-stratification and to guide treatment selection. These include markers of bone metabolism, circulating tumour cells, and DNA as well as imaging biomarkers such as SUVmax and metabolic volume on FDG PET, which are already in use in the metastatic castrate resistant setting. As the deluge of treatment options comes, there is a need to further refine our treatment of mHSPC. This may entail having a balanced approach by defining specific patient populations who will benefit most not only from treatment intensification but also de-escalation, with what agents, and for what duration.

Table: Current trials evaluating novel therapies and treatment combinations in patients with mHSPC

Trial	Experimental intervention	Disease group	Phase	Primary outcome
177Lu-PSMA
UpfrontPSMA (NCT04343885)	LuPSMA + Docetaxel	De novo, high volume mHSPC	II	Undetectable PSA at 12 months
PSMAaddition (NCT04720157)	LuPSMA + SOC	mHSPC	III	rPFS
NCT05079698	LuPSMA + SABR	Relapsed oligometastatic mHSPC	I	Proportion of patients with DLT
PARP inhibitors
FAALCON (NCT04748042)	Olaparib + abiraterone + SABR	Relapsed oligometastatic mHSPC	II	Percentage of patients without treatment failure at 24 months
TRIUMPH (NCT03413995)	Rucaparib	Germline HRD mutant mHSPC	II	PSA-RR
NCT04734730	Talazoparib + abiraterone	mHSPC	II	PSA nadir <0.2 at 12 months
ZZ-first (NCT04332744)	Talazoparib + enzalutamide	High volume mHSPC	II	PSA-complete response
TALAPRO-3 (NCT04821622)	Talazoparib + enzalutamide	DDR-mutated mHSPC	III	rPFS
AMPLITUDE (NCT04497844)	Niraparib + Abiraterone	HRD mutant mHSPC	III	rPFS
MAGNITUDE (NCT03748641)	Niraparib + Abiraterone	HRD mutant + wild-type mHSPC	III	rPFS
AKT inhibitors
CAPItello281 (NCT04493853)	Capivasertib + abiraterone	De novo mHSPC, PTEN deficiency confirmed on IHC	III	rPFS
CDK4/6 inhibitors
CYCLONE-3 (NCT05288166)	Abemaciclib + abiraterone	High-risk mHSPC	III	rPFS
PD-1/PD-L1 inhibitors
CABIOS (NCT04477512)	Cabozantinib + abiraterone + nivolumab	mHSPC	I	Frequency of DLTs
NCT04262154	Abiraterone + atezolizumab + SABR	De novo mHSPC	II	Failure-free rate at 2 years
MAGIC-8 (NCT03689699)	Nivolumab + BMS986253	Relapsed low-volume mHSPC	I/II	Rate of PSA recurrence, safety and tolerability
POSTCARD (NCT03795207)	Durvalumab + SABR	Relapsed low-volume mHSPC (visible on PET scan only)	II	2 years PFS

Written by: Arun Azad¹ Kenneth Chen,² & Louise Kostos¹

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
Department of Urology, Singapore General Hospital, Singapore, Singapore

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