ASCO 2023: When Less Is More: Decreasing Exposure to Systemic Therapy for Hormone-Sensitive Prostate Cancer

(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2^nd and June 6^th was host to a session on prioritizing and sequencing therapy for advanced prostate cancer. Dr. Anis Hamid discussed the current treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC), debating against routine, early treatment intensification for mHSPC patients and arguing that ‘less is more’ in this scenario.

Dr. Hamid began by presenting the case of a 66-year-old male who underwent a radical prostatectomy in 2010 for Grade Group 3 disease, subsequently received salvage radiotherapy + a short course of ADT three years later in 2013, and then was started on doublet ADT+ abiraterone/prednisone 4 years later when he was found to have metachronous, CHAARTED low-volume, LATITUDE low-risk disease on PSMA PET imaging. PSMA PET IMAGE
This patient subsequently had an excellent PSA response with a PSA of 0.05 ng/ml within 6 months of initiating treatment. 6 years later the patient remained on continuous therapy with undetectable PSA levels, but with mild-moderate side effects, including grade 1+ fatigue, tolerable hot flashes, easy bruising, and osteopenia on bone densitometry. Dr. Hamid asked: Is this patient a suitable candidate for treatment de-intensification in this setting? 6 months after adt
When considering systemic treatment options for mHSPC patients, it is important to consider the timing of disease presentation (synchronous versus metachronous) and the volume of disease (high versus low volume). Differences in clinical outcomes by disease volume and presentation/timing are reproducible across clinical trials and retrospective/registry datasets. When considering these two variables in tandem, four distinct mHSPC subgroups become clinically relevant (median overall survival [OS] per CHAARTED and GETUG-15):

Metachronous and low volume: ~8 years
Metachronous and high volume: 4.5 years
Synchronous and low volume: 4.5 years
Synchronous and high volume: 3 years

The recently published update of the ENZAMET trial clearly demonstrates this whereby patients with metachronous, low volume disease had significantly better 5-year cancer-specific survival rates (90%), compared to patients with synchronous, high-volume disease (58%). We also need to consider the competing risk of death from other causes, which occur in 44% of patients in the metachronous, low volume group within 5 years of randomization, compared to only 12% of patients in the higher risk group of synchronous, high-volume disease.¹ These data suggest adopting less aggressive, risk-adapted approaches in these metachronous, low volume mHSPC patients, sparing them the toxicity of additive treatment intensification. ENZAMET 5 year Furthermore, we need to consider patients’ concerns in this setting. While the ASCO 2020 National Cancer Opinion Survey demonstrated that dying from cancer was the patients’ greatest concern regarding being diagnosed with cancer (62%), other significant concerns included the side effects of treatment (60%), long-term complications (42%), and the financial fears of financial impact on the family (34%) and paying for treatment (28%). This highlights the importance of considering other patient-relevant issues, beyond just OS outcomes, when considering treatment intensification. ASCO 2020
Patient-reported outcomes (PROs) from androgen receptor signaling inhibitor (ARSI) doublet therapy trials clearly demonstrated that ARSIs are associated with improvements in health-related quality of life (HRQoL) measures, time to pain progression, and other symptoms and functional domains, including in high-risk mHSPC populations. These benefits are most prominent early on with these treatments and likely reflect early enhanced disease control with treatment intensification.² LATITUDE We also note an early decline in key symptom domains followed by stable differences thereafter, with cross-over in time to deterioration likely owing to improved disease control.^1,3 TITAN fatigue intensity
In addition to disease volume and timing/presentation, can we use other biomarkers to guide treatment (de)intensification approaches? The best characterized response-based endpoint that guides prognosis in mHSPC patients is the PSA nadir within 6 months of treatment initiation. Achieving a 6-month PSA nadir of <0.1 ng/ml has been consistently shown to be associated with improved survival endpoints across the major trials in the mHSPC disease space. As such, patients achieving this landmark may be suitable candidates for treatment de-intensification. Trial comparison table
This is further highlighted by a recent report from the TITAN trial that demonstrated that early (3 months) and deep PSA responses with an ADT + an ARSI are associated with significantly prolonged OS (HR: 0.35, 95% CI: 0.25 – 0.48).⁴ TITAN PSA response
Although it is clear that early PSA response is a strong prognostic biomarker, there is still a paucity of high-level, prospective data to inform the decision for continuous versus intermittent treatment strategies in the era of combination systemic therapy. The SWOG 9346 trial by Dr. Hussain et al. randomized mHSPC patients with a PSA of 5 ng/ml or higher to receive combined ADT for 7 months following which patients with a PSA of 4 ng/ml or less were randomized to either continuous or intermittent ADT. This trial demonstrated the non-inferiority of intermittent ADT in this setting (HR for intermittent ADT: 1.10, 90% CI: 0.99 – 1.23), with benefits in the following quality of life domains: mental health, physical functioning, erectile function, and libido at 9 months favoring intermittent therapy.⁵ However, whether we can translate the results of this study to the doublet/triplet therapy setting remains to be determined.
survival over time
Currently, trials are underway attempting to address this clinical question. The A-DREAM trial is a phase 2 trial of ADT interruption in patients responding exceptionally to ARSIs in mHSPC. Patients with a PSA <0.2 ng/ml after 18-24 months of ADT and 12 months of an ARSI will be offered treatment interruption, with triggers for re-initiation including a PSA rise to 5 ng/ml or higher and/or development of radiographic changes or prostate cancer-related symptoms. ADREAM trial
Similarly, the DE-ESCALATE trial, a phase III pragmatic trial, will evaluate intermittent ADT in the era of ARSIs, with treatment suspensions offered to patients who achieve a PSA of 0.2 ng/ml or less following 6-12 months of ADT + ARSI +/- docetaxel. DE ESCALATE
What about metastasis-directed therapy in the mHSPC disease setting. STOMP was a phase II trial of oligorecurrent mHSPC with 3 or less lesions on choline PET/CT. Patients randomized to MDT, in the form of SABR or surgery, had significantly prolonged ADT-free survival (21 versus 13 months).⁶ORIOLE similarly evaluated MDT (SABR) in oligorecurrent mHSPC patients with 3 or less lesions on conventional imaging. Patients treated with MDT had significantly improved 6-month progression rates (61% versus 19%). This benefit was most pronounced in patients who had all PET-detected lesions targeted by MDT treatment plans.⁷ A pooled analysis of the two trials published in 2022 demonstrated that there was a proportion of these mHSPC patients (15-20%) treated with MDT who had PFS beyond 4 years. Notably, the median rPFS with MDT and in the no high-risk mutations cohort was 25.3 months.⁸ PFS OS
The recently published EXTEND trial evaluated the utility of adding MDT to intermittent hormonal therapy. This phase II trial randomized patients with oligometastatic hormone-sensitive or resistant prostate cancer (0-5 lesions) to six months of hormonal therapy followed by intermittent hormonal therapy with or without MDT. This trial met its primary endpoint with prolonged PFS in the MDT arm (HR: 0.25, p<0.001). Notably, a benefit was observed in the mHSPC subgroup (HR: 0.22), with consistent benefits across subgroups, including: synchronous versus metachronous and ADT + ARSI versus ADT alone.⁹ Significantly, eugonadal PFS (i.e., PFS in those who recovered normal testosterone levels following intermittent hormone therapy suspension) was significantly prolonged in the MDT group (HR: 0.32, 95% CI: 0.11 – 0.91, p=0.03).
PFS combined therapy vs hormone therapy
Non-castrating approaches are also being evaluated in select mHSPC populations with ¹⁷⁷Lu-PSMA-617 recently evaluated as monotherapy for patients with metachronous, low-volume mHSPC disease with promising initial results. PSA 50
Other trials in this space include DART (SABR +/- 6 months of darolutamide) and RAVENS (SABR +/- Ra-223).

Dr. Hamid noted that other biomarkers in this setting, beyond PSA, are emerging and include lower tumor copy number alterations, which are associated with reduced risk of progression and death in the STAMPEDE ADT arm, and transcriptional subtypes (luminal-basal, AR activity, and Decipher® risk grouping) recently assessed within the CHAARTED ADT arm.
Dr. Hamid concluded his presentation with his thoughts on future directions in adaptive de-escalation in mHSPC.
Future directions for mhspc
Presented by: Anis Hamid, MBBS, GU Oncology Research Fellow, Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia