The Past, Present, and Future of Treatment Intensification for Metastatic Hormone–Sensitive Prostate Cancer

Oncology's success stories, durable remissions or cures for advanced cancers, have historically been achieved using multiagent frontline treatment regimens. Examples of successful treatment intensification—the addition of rituximab to CHOP chemotherapy for diffuse large B-cell lymphoma or the three-drug regimen of bleomycin, cisplatin, and etoposide for disseminated germ cell tumors—demonstrate the benefits of early utilization of therapies with distinct mechanisms of action to overcome diverse resistance mechanisms.^1,2 Building on the efficacy of androgen-deprivation therapy (ADT), the frontline treatment options for patients with metastatic hormone–sensitive prostate cancer (mHSPC) have evolved in recent years with treatment intensification strategies used to improve survival and delay disease progression. Doublet therapy, the addition of either docetaxel chemotherapy or one of multiple approved androgen receptor signaling inhibitors (ARSIs) including abiraterone acetate, apalutamide, or enzalutamide, to ADT, improved survival over ADT alone, becoming a standard of care.^3-7 Recently, further intensification of up-front therapy with triplet therapy (docetaxel + ARSI + ADT) demonstrated improved overall survival (OS) compared with docetaxel + ADT in two randomized control trials, PEACE-1 and ARASENS, supporting triplet therapy as a new standard-of-care option for some patients with mHSPC.^8,9 In addition, radiation to the primary has emerged as a life-prolonging component of treatment intensification for men with low-volume de novo disease by conventional imaging.¹⁰ Despite these successes, questions remain as to how to select patients most likely to benefit from intensification of systemic, local, or metastasis-directed therapy and how to improve frontline therapy for mHSPC further.

THE TAKEAWAY

• In the article¹¹ that accompanies this editorial, efficacy and safety analyses in subgroups on the basis of metastatic disease volume and risk from the phase III ARASENS trial, which previously demonstrated the benefit of darolutamide added to androgen-deprivation therapy + docetaxel for patients with metastatic hormone–sensitive prostate cancer, show that the survival benefit of triplet therapy is seen across volume and risk subgroups, although the benefit in patients with low-volume disease is less clear. Triplet therapy should be considered a standard of care for patients with metastatic hormone–sensitive prostate cancer, particularly for patients with high-volume metastatic disease.

Efforts to risk stratify patients with more aggressive mHSPC that may benefit most from intensified frontline therapy have centered around metastatic disease volume, distribution of metastases, and other markers of aggressive disease biology. In the phase III CHAARTED trial evaluating docetaxel + ADT compared with ADT alone in patients with mHSPC, patients were stratified by disease volume, with high-volume disease defined as visceral metastases and/or four or more bone metastases on conventional computed tomography/magnetic resonance imaging or bone scan with at least one outside the vertebral column and pelvis.⁷ In the phase III LATITUDE trial evaluating the addition of abiraterone to ADT, patients with mHSPC were classified as having high-risk disease on the basis of at least two of the following criteria: Gleason score ≥ 8, three or more bone lesions, and the presence of visceral metastases.⁶ Another important risk factor, the presence of metastatic disease at initial prostate cancer diagnosis (synchronous/de novo) is associated with worse outcomes compared with developing metastases after local therapy for prostate cancer (metachronous/recurrent) and another potential way to risk stratify patients with mHSPC. In PEACE-1 and ARASENS, the addition of a concurrently administered ARSI (abiraterone and darolutamide, respectively) resulted in significantly improved OS compared with docetaxel + ADT in the overall study populations.^8,9 In PEACE-1, when stratified by disease volume, a clear benefit was seen with the addition of abiraterone to docetaxel + ADT in patients with high-volume disease, but this benefit was not yet observed in the low-volume group as data remain immature and underpowered and thus any potential OS benefit in this population remains unclear.⁸ Contrastingly, patients in ARASENS were not stratified by disease volume or risk and in the initial publication of results, and data were not reported for these subgroups.⁹

In the article accompanying this editorial, the authors of the ARASENS trial present post hoc subgroup analyses of patients by disease volume or risk, defined by the CHAARTED and LATITUDE criteria, respectively.¹¹ In these subgroup analyses, the addition of darolutamide to docetaxel + ADT resulted in improved OS in patients with high-volume, high-risk, and low-risk disease, but this benefit was not clearly seen in the low-volume subgroup for which the hazard ratio for OS crossed 1 (hazard ratio, 0.68; 95% CI, 0.41 to 1.13). The authors also report improved secondary end points, including time to castration resistance and time to subsequent therapy, in all volume and risk subgroups, but it is not known if these secondary outcomes are surrogates for OS in this mHSPC setting. Adverse events were similar between treatment groups and across subgroups. In interpreting these data, it is important to note that the majority of patients enrolled in ARASENS had high-volume (77%) and/or high-risk (70%) disease, resulting in low event frequencies in the low-volume and low-risk subgroups and limiting the ability to draw conclusions in these historically more favorable subgroups. Previously reported at the time of initial publication, subgroup analyses of patients with synchronous or metachronous metastatic disease demonstrated improved outcomes in both settings; however, the metachronous subgroup was small (14% of the study population).⁹ As the majority of patients had synchronous/de novo, high-volume and/or high-risk disease, there was insufficient power to further subdivide the volume and risk groups by de novo/recurrent metastases. Thus, it remains unclear whether the improved outcomes seen in the metachronous group were driven by patients with otherwise high-volume/high-risk disease. This is of interest as patients with metachronous mHSPC often have low-volume disease after being observed closely after initial localized therapy and generally have more indolent, hormone-responsive disease with disease benefit from an ARSI + ADT doublet, where the benefit of added docetaxel chemotherapy is unclear.¹²

Hussain et al¹¹ should be commended for their efforts to add granularity to their previously published results from the ARASENS trial, which established upfront triplet therapy with ADT, docetaxel, and darolutamide as a standard-of-care option for patients with mHSPC. Given the clear survival benefit demonstrated with the combination of ARSI + docetaxel + ADT in both ARASENS and PEACE-1, triplet therapy should now be considered for some patients with mHSPC, particularly those with high-volume de novo metastatic disease and who are fit for chemotherapy (Fig 1). If patients do not receive concurrent docetaxel + ARSI (abiraterone or darolutamide), sequential administration of enzalutamide or apalutamide after docetaxel can be considered as the registrational trials of enzalutamide and apalutamide allowed some patients to receive prior docetaxel, demonstrating the safety and potential efficacy of sequential use of these ARSIs after docetaxel in combination with ADT. These trials were not, however, designed or adequately powered to evaluate the potential efficacy of triplet therapy.^3-5 In addition, other life-prolonging treatment intensification strategies should be discussed, especially radiation to the prostate for patients with low-volume de novo mHSPC.¹⁰ Still, questions remain as to how best to apply these findings in clinical practice and whether all patients, particularly patients with low-volume, metachronous metastatic disease benefit from the addition of docetaxel chemotherapy to ADT + ARSI frontline therapy. Given the small number of patients with metachronous low-volume disease in ARASENS, it is not possible to examine the potential benefit of triplet therapy in this population. In the doublet setting, the benefit of frontline docetaxel has been most pronounced in the high-volume setting with mixed results in patients with low-volume disease. In CHAARTED, which included patients with de novo or recurrent mHSPC, an OS benefit was observed for patients with high-volume disease whereas no OS benefit was observed for patients with low-volume disease.⁷

FIG 1.

Proposed treatment approach for mHSPC on the basis of disease volume (high-volume v low-volume) and timing of metastatic disease development (synchronous/de novo v metachronous/relapsed). High-volume disease is defined as visceral metastases and/or ≥4 bone metastases with at least one outside of the vertebral column and pelvis on the basis of CHAARTED criteria. De novo mHSPC is defined as metastatic disease at the time of initial prostate cancer diagnosis. Relapsed/metachronous mHSPC is defined as metastatic disease identified after initial diagnosis and treatment for localized prostate cancer. Assessments are made using conventional imaging (computed tomography and bone scan). In all settings, a clinical trial should be considered to further evaluate optimal treatment strategies and improve outcomes. ADT, androgen-deprivation therapy; ARSI, androgen receptor signaling inhibitor; mHSPC, metastatic hormone–sensitive prostate cancer.

In the United States, where real-world data suggest that <10% of patients with mHSPC receive docetaxel, the potential added benefit of docetaxel to frontline ARSI + ADT would be the most relevant contemporary question which has not been addressed in a randomized clinical trial.¹³ However, given the comparable efficacy of docetaxel and ARSIs in the STAMPEDE trial, this is generally assumed.¹⁴ Regardless of the chosen treatment intensification strategy, whether an ARSI + ADT doublet or docetaxel-containing triplet therapy, it remains critical to ensure that patients are gaining equitable access to these therapies in clinical practice as real-world data suggest that many men with mHSPC remain undertreated by receiving ADT alone.^13,15,16

Despite these increasingly effective treatment intensification strategies in mHSPC, in general, permanent remissions and the ability to stop therapy remain elusive goals. At the same time, a one-size-fits-all approach to treatment intensification in patients with mHSPC likely results in some patients being overtreated, exposing them to additional therapies and associated toxicities that may not be needed to treat more indolent disease. Future efforts to optimize frontline treatment intensification for patients with mHSPC need to emphasize development of more effective combination regimens but also identification of prognostic and predictive biomarkers that may help select patients most likely to benefit from specific therapies. How to incorporate more sensitive imaging modalities such as prostate-specific membrane antigen positron emission tomography-computed tomography, metastasis-directed therapy, and genomic alterations and novel precision therapies such as poly (ADP-ribose) polymerase inhibitors into this frontline decision making remain important questions to address in prospective clinical trials. Along with evaluation of progressively intensified triplet and even quadruplet therapies, assessment of new therapies that may replace docetaxel with drugs that maintain or even further improve survival and quality of life while introducing less toxicity and the potential to stop systemic therapy at some point are of importance. For now, given the imperfection of our current patient selection strategies, early treatment intensification is an important standard of care to consider for patients with mHSPC to maximize the potential benefit of these therapies and improve long-term survival for all patients.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Administrative support: Andrew J. Armstrong

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The Past, Present, and Future of Treatment Intensification for Metastatic Hormone–Sensitive Prostate Cancer

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