Metastatic Prostate Cancer: Optimization of Systemic Treatment

Massive increases in prostate cancer incidence are expected worldwide due to aging populations (1). Therefore, improving the clinical management of patients with advanced prostate cancer is an important issue. Multiple trials have shown improved survival in the high-risk setting due to the intensification of systemic treatment, which resulted in the approval of a range of agents and combinations. However, implementing insights from trials in clinical practice still constitutes a challenge, particularly for the elderly. According to data from the SEER and VHA databases, median overall survival has been improving in younger patients diagnosed with metastatic prostate cancer between 2000 and 2019, while hardly any change has occurred in men aged ≥80 years (2).

Data from the UK show that a large proportion of patients are still treated with androgen deprivation therapy (ADT) alone for metastatic hormone-sensitive prostate cancer (mHSPC) although guidelines advise against an ADT-only approach in fit individuals (3). Global underutilization of guideline-recommended survival-prolonging therapy is an established fact that calls for optimization of systemic treatment.

mHSPC as a spectrum

Various drugs and combinations are available in fit patients with mHSPC in addition to ADT. In high-volume disease, abiraterone/prednisolone, apalutamide or enzalutamide can be added, as well as docetaxel alone or together with abiraterone/prednisolone or darolutamide. Patients with low-volume mHSPC benefit from ADT plus abiraterone/prednisolone, apalutamide, enzalutamide, and irradiation to the primary tumor. Potentially, radiation to oligometastatic disease can be used, as well as chemotherapy with or without abiraterone/prednisolone or darolutamide.

In light of these numerous choices, treatment selection requires thinking of the disease as a spectrum. Men with indolent biology may benefit from the intensification of local therapy, while de-escalation of systemic therapy is an option. On the other hand, there are those with very aggressive disease who might not be fit enough to receive treatment at the time of progression. These patients are more likely to benefit from more intensified systemic therapy as their first-line treatment.

Definitions of disease volume/risk in clinical trials vary based on imaging, thus dividing patients in a slightly artificial manner. In the CHAARTED study, high-volume disease was defined as ≥4 bone metastases including ≥1 outside the vertebral column or pelvis and/or visceral metastases (4). In LATITUDE, the term “high-risk” was used, which was ≥2 high-risk features including ≥ 3 bone metastases, visceral metastasis, and ISUP grade ≥4 (5). However, the only differentiation included in the guidelines relates to the decision of whether to administer radiation therapy to the primary tumor or not. Low-volume disease is currently the only area where we are using this clinical distinction. De-escalation of treatment in patients with excellent PSA responses is currently a hot topic. For instance, in STAMPEDE, over half of patients in the M1 low-volume cohort treated with ADT and abiraterone had not relapsed after seven years (6). Ongoing and planned trials will attempt to find answers here.

Lack of predictive biomarkers

Regarding the question of treatment intensification in aggressive disease, a recent meta-analysis has demonstrated that patients with high-volume mHSPC derive the highest effect size with triplet therapy rather than doublet therapy (7). However, while many prognostic markers have been defined, predictive markers are still lacking, and no prospective studies validating markers of interest for treatment selection have been published to date. Ongoing trials such as CAPItello-281 and AMPLITUDE studies are using biomarkers for patient stratification, however.

We can all help to identify and overcome some of the barriers to implementation of evidence-based practice. First-line treatment selection involves assessment of our patients, their preferences, access and disease characteristics. As the PSA nadir has shown to be prognostic, poor responders should be monitored carefully, and future intensification of treatment should be considered. Patients with advanced prostate cancer are generally living longer today, which means that we need to be proactive about monitoring their bone and cardiovascular health.

mCRPC: the question of sequencing

Similar to mHSPC, a multitude of trial data has been obtained in the setting of metastatic castration-resistant prostate cancer (mCRPC), and many treatments to consider, such as radioligand theranostics, androgen receptor pathway inhibitors and PARP inhibitors, have become available. The treatment choice depends on factors such as the disease trajectory, symptoms, patient preferences and co-morbidities. Considering this multitude of options, sequencing is increasingly becoming challenging. PET PSMA, germline/somatic homologous recombination repair mutations, somatic microsatellite instability and other rare tumor-agnostic biomarkers are used to select treatment.

The first- and second-line choices for the treatment of mCRPC depend on the agent(s) previously administered for mHSPC (Table 1). Particularly in the first-line setting after combined mHSPC therapies, some combinations are not supported by a wealth of evidence; here, our clinical judgment should come into play. This is the space where we are waiting for more data, both from clinical trials and real-world studies. New findings imply that some patients might have access to theranostic treatment before chemotherapy in the future. In the phase III PSMAfore study, the use of 177Lu-PSMA-617 has led to improved progression-free survival in patients with mCRPC who were chemotherapy-naïve.8 However, overall survival data are immature for the time being.

Table 1. First- and second-line options in patients with mCRPC according to pretreatment for mHSPC

HRRm, homologous recombination repair mutation; MSI-H, high microsatellite instability

Multidisciplinarity at all times

Taken together, imaging and genomic biomarkers are becoming increasingly important for planning the treatment of patients with mCRPC. Clinical trials are currently testing novel therapies and combinations much earlier in the course of the disease. While standards of care are evolving rapidly with new approvals, multi-disciplinary management remains essential, not only at diagnosis, but also at progression. As a community, we definitely need to advocate for all of our patients to benefit from available new therapies and ongoing research efforts.

To learn more, don’t miss our roundtable session on prostate & urothelial cancer by Dr. Aurelius Omlin

References:

1. Zhang W et al: Global burden of prostate cancer and association with socioeconomic status, 1990-2019: A systematic analysis from the global burden of disease study. J Epidemiol Glob Health 2023; 13: 407-21
2. Schoen MW et al: Survival in patients with de novo metastatic prostate cancer. JAMA Netw Open 2024; 7: e241970
3. Dodkins J et al: Utilisation rates of treatment intensification for metastatic hormone sensitive prostate cancer in England, UK. ESMO 2023, poster 1790P
4. Kyriakopoulos CE et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018; 36: 1080-7
5. Fizazi K et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. Engl J Med 2017; 377: 352-60
6. Parker CC et al: Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med 2022; 19: e1003998
7. Hoeh B et al: Triplet or doublet therapy in metastatic hormone-sensitive prostate cancer: Updated network meta-analysis stratified by disease volume. Eur Urol Focus 2023; 9:838-842
8. Sartor O et al: Phase III trial of [177Lu] Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol 2023; 34 (suppl_2): S1254-S1335