MDT Viable for Patients With Metastatic HSPC Wanting to Defer Systemic Therapy

In a recent interview with Oncology Learning Network, Neil R. Parikh, MD, Resident Physician, Department of Radiation Oncology, University of California – Los Angeles, discussed the findings and clinical significance of a recent study that he and his team of co-investigators, including Phuoc T. Tran, MD, PhD, Associate Professor of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, and Amar U. Kishan, MD, Assistant Professor, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, conducted.

The study by Dr Parikh and colleagues focused on the cost-effectiveness of using metastasis-directed therapy (MDT) in the treatment of patients with oligometastatic hormone-sensitive prostate cancer (HSPC), and evaluated how it compares with androgen deprivation therapy (ADT).

From left to right: Phuoc T. Tran, MD, PhD, Amar U. Kishan, MD, and Neil R. Parikh, MD.

What existing data led you to evaluate the cost-effectiveness of using MDT in this setting?

MDT has recently become an exciting new addition to the treatment paradigm of metastatic HSPC patients, especially after results from the STOMP trial were published in late 2017. The randomized STOMP study successfully proved the effectiveness of MDT in delaying initiation of ADT in patients with oligorecurrent disease; this was largely important as it opened up a potential treatment option for patients not keen on immediately starting ADT—either because of lifestyle preferences, comorbidities, or otherwise.

From a value perspective, MDT is an attractive concept as it allows patients to enjoy improved quality-of-life when off ADT, while saving health systems significant resources that would have otherwise gone to hormonal therapy during this time. The cost savings during this period become especially large if the alternative includes abiraterone in addition to ADT (which is likely the new standard-of-care for metastatic HSPC per the recent STAMPEDE and LATITUDE trials).

The flipside of MDT, of course, is its uncertain impact on the natural history of oligorecurrent prostate cancer. Does ADT-free survival directly translate to increased time to castrate-resistance, and increased overall survival? Or instead, do we find that patients initially receiving MDT have a less favorable treatment course upon eventually starting hormonal therapy? Time will eventually tell, as several ongoing trials are actually looking to answer this specific question. 

Given these open questions, our goal was to use data currently available in literature at this time to determine the cost-effectiveness of treating oligorecurrent patients with MDT prior to systemic therapy compared to systemic therapy upfront.

Please briefly describe your analysis and its findings. Were any outcomes particularly surprising?

To perform our analysis, we built a Markov model comparing 3 different treatment strategies of patients with oligorecurrent disease—(1) MDT followed by salvage abiraterone plus ADT; (2) abiraterone plus ADT upfront; and (3) ADT upfront.

Patients in each arm were assumed to have oligorecurrent disease (defined as 1-3 extracranial lesions; primary controlled) and were considered "low-risk" hormone-sensitive patients; patients who eventually failed MDT developed polymetastatic disease and were then considered "high-risk" hormone-sensitive patients. How quickly patients suffered progression of disease (and ultimately death) was based on data from 3 major sources, including the STOMP publication, STAMPEDE publication, and STAMPEDE M1 sub-analysis. This analysis utilized a time horizon of 10 years, willingness-to-pay incremental cost–effectiveness ratio (ICER) threshold of $100,000, and 3-fraction stereotactic body radiation therapy (SBRT) utilized for MDT. Costs were taken from Medicare schedules, with utilities taken from the literature.

Of the 3 strategies, at 10 years, MDT was found to be the most cost-effective. Compared to ADT alone (cost of ~$230,000 and effectiveness of ~3.2 quality-adjusted life year [QALY]), both MDT upfront (~$350,000 and ~4.5 QALY) and abiraterone plus ADT upfront (~$630,000 and ~4.7 QALY) were found to have higher costs and higher effectiveness. When comparing ICERs, this translated to ~$90,000 per QALY for MDT (deemed "cost-effective" below the $100,000 threshold) and ~$260,000 per QALY for abiraterone plus ADT upfront (not cost-effective). When only comparing abiraterone plus ADT upfront versus MDT upfront, MDT was found to be more cost-effective, even after performing a variety of 1-way sensitivity analyses modifying various model inputs. 

The most surprising aspect of these findings was precisely how influential the price of abiraterone is to the model's findings. In our model, the price of abiraterone would have had to drop by 88% for the abiraterone plus ADT arm to become cost-effective compared to MDT.

What are the possible real-world applications of these findings in clinical practice? How can these findings affect the treatment landscape for these patients?

Our preliminary analysis further confirms that MDT appears to be a viable treatment strategy for patients wishing to defer systemic therapy. Although at 10 years, our model predicted a higher percentage of patients alive with metastatic HSPC in the abiraterone plus ADT group (~30%) compared to the MDT group (~16%), the improvement in quality-of-life during MDT nearly offsets this difference, resulting in similar effectiveness values.

These findings hopefully provide confidence to physicians to initiate discussion regarding MDT with their oligorecurrent patients—especially those who have clearly expressed prioritization for quality-of-life or have medical comorbidities which would make hormonal therapy not well-tolerated.

From a health-systems perspective, these preliminary findings illustrate tremendous value with sequencing MDT prior to systemic therapy. It would thus be largely beneficial for Medicare, private payors, and any accountable care organizations bearing financial risk of patients to explore and encourage the use of SBRT in patients with oligorecurrent disease. 

Do you and your co-investigators intend to expand upon this research? If so, will you be incorporating any new cost interventions, end points, or patient populations?

We plan to update our preliminary findings to incorporate the eagerly-anticipated publication of the M1 STAMPEDE sub-analysis, select data of which were presented by Alex Hoyle at ESMO 2018. Although our model has already incorporated data from limited survival curves based on LATITUDE risk stratification, we look forward to seeing the team's final results, with similar survival curves published utilizing CHAARTED criteria to classify low- and high-risk patients.  

The next stage of our work will also include multivariate probabilistic sensitivity analyses, allowing us to determine the full range and distribution of cost-effectiveness results. 

Looking forward, there are currently several ongoing trials in the oligorecurrent population studying the true effect of MDT on survival, local control, time to development of CRPC, toxicity, and quality-of-life. As we study more patients receiving MDT, follow these patients for longer durations, and understand the effect of MDT on the natural history of oligorecurrent disease, we will have additional opportunities to further hone our model's assumptions and subsequent results.

Finally, given the separate benefits illustrated by MDT and advanced ADT in the oligorecurrent setting, a future opportunity exists to study the combination of MDT with upfront systemic therapy in patients with oligorecurrent disease. However, prior to determining the cost-effectiveness of such a combination, it is imperative that we sufficiently evaluate the clinical feasibility and efficacy of this regimen.

Source: Parikh NR, Nickols NG, Rettig M, et al. Cost-effectiveness of metastasis-directed therapy in the setting of oligometastatic hormone-sensitive prostate cancer. Presented at: the 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 147.