Treatment of primary in M1 HSPC: Not yet ready for prime time as standard of care

The increasing incidence of hormone sensitive metastatic prostate cancer (M1 HSPC) is likely partially due to changes in screening practices and also increased sensitivity of staging modalities [1]. The current front-line treatment options for de novo metastatic prostate cancer (PCa) include Androgen Deprivation Therapy (ADT), chemohormonal therapy (ADT + 6 cycles of docetaxel) (based on the CHAARTED, STAMPEDE arm C, and GETUG-AFU 15 trials), and ADT plus abiraterone for any M1 HSPC (based on the LATITUDE and STAMPEDE arm G clinical trials) [2–6]. Practical algorithms have been suggested to guide choice between these options in patients with high volume metastases, but there is variability to how these systemic agents are applied in clinical practice. This issue is becoming even more complex with recent and ongoing phase III studies evaluating the addition of androgen axis inhibitors, enzalutamide, apalutamide, darolutamide, and orteronel in M1 HSPC compared to ADT alone. A complicated systemic therapy backdrop with inadequate understanding of biological mechanism of prolonged reponders, early castration resistance, and oligoprogression pattern differences among therapies, along with the prolonged time frames for clinical trials to mature, makes a “standard’ approach to de novo metastatic prostate cancer presently undefined. With renewed interest in treating all identifiable disease sites in the metastatic setting, there are many trials evaluating local therapy and/or metastasis directed therapies in this patient population. Currently data exists, largely in combination with ADT alone, that suggests a benefit of local radiotherapy, in low volume metastatic patients, but should this be standard of care in contemporary practice [7]?

Until recently, all data regarding local therapy in M1 HSPC has been retrospective. Several of these studies have reported higher OS (overall survival) and DSS (disease specific survival) with cytoreductive prostatectomy (CRP) compared to radiotherapy (RT), Brachytherapy or no surgical treatment, with “optimal survival benefits” seen in those with M1a disease, suggesting a role of CRP in this setting [8–11]. Whether this is purely a result of selection bias or is a result of tumor debulking remains to be seen. We do know that CRP is a safe procedure in well selected patients, with M1 HSPC, with a potential for reduction of local recurrence and late local complications [12]. DSS and OS benefit have also been retrospectively demonstrated with RT to the primary compared with systematic treatment or observation alone. [8–11, 13]. However, many of these studies had no information on volume or location of metastases detected, using conventional imaging methods and lacked data regarding systemic treatments.

Recently, the HORRAD study randomized 432 men with M1 HSPC to ADT with radiotherapy to the prostate or ADT alone [14]. This study recruited slowly over an extended time period, the power of the study was limited by its small size and the study inclusion criteria selected more men with high volume metastases (as reflected by median PSA of 142). The results of HORRAD favor the null hypothesis of no OS benefit with radiotherapy combined with ADT in the whole trial population at a median follow up of 47 months. A post-hoc sub-group analysis of patients with <5 osseous metastases based on conventional bone scan very weakly favored the alternative hypothesis that radiotherapy combined with ADT provides an OS advantage. Notably the precision of that subgroup analysis was low with very wide 95% CI noted (HR 0.68; 95% CI 0.42–1.1).

These results were followed closely by publication of data from arm H of the STAMPEDE trial [7]. This study of 2061 men, which was well powered to address the primary endpoint and two subgroup analyses, randomized men with metastatic HSPC to standard of care (ADT), which changed over time to ADT +/− docetaxel or standard of care with radiotherapy to the prostate. Consistent with HORRAD, the results of STAMPEDE strongly favored the null hypotheses of no OS benefit in the population as a whole. However, a sub-group analysis of men with low volume disease, according to CHAARTED criteria , showed that men receiving primary site radiotherapy had better OS compared with those who did not receive radiotherapy (81% vs 73%; HR =0.68; 95% CI 0.52–0.90, p=0.007) with a mean 3.6 month improvement in survival at 3 years, median not reached for either group. Interestingly, this subgroup analysis was planned prior to commencing data analysis, but not from the study outset.

Although the sub-group analysis of STAMPEDE Arm-H provides an encouraging signal of benefit derived from definitive treatment of the primary tumor with radiation in low volume M1 HSPC, there are a number of key limitations, which must be considered. The analysis was premature in that it was powered at 60% assuming a 72-month OS in the low volume group, but only 25% of events had occurred at the time of reporting and only 26 patient deaths separated the two groups. Of note, subgroup analyses of trials with overall non-significant results are hindered by substantial inflation of type I error, and thus the p-value significance threshold should be appropriately adjusted ideally to <0.004 (one-sided) to improve the probability that the observed difference is not a chance finding [15]. The generalizability of these results to present day is also unclear as no patient received abiraterone in addition to ADT and a minority (16%) received docetaxel. Additionally, early systemic treatment resistance was not quantified. Finally, the radiation dose used in the study was less than the standard dosing (36Gy over 6 weeks of 6Gy or 55Gy in 20 daily fractions of 2.75Gy over 4 weeks 9). Thus, it is perhaps not surprising that there was no difference in symptomatic local progression between the groups (42% control vs 44% radiotherapy), but as stated by the authors this endpoint was considered too early to assess. It is unclear as to why the authors deemed that the local progression data was too immature to asses (which would be expected to precede the reported OS). Both the HORRAD and STAMPEDE arm H data provide further support to ongoing trials that seek to add to the quality of the prospective data using application of contemporary systemic agents in combination with local therapies. The use of radiation to the primary in men with low volume M1 HSPC may be a consideration in the setting of ADT use alone (i.e. unavailability of abiraterone and/or contraindication to docetaxel), but outside of this rare situation in contemporary practice, its benefit remains unproven and patients should be counseled regarding ongoing equipoise in the field and need for further information gleaned from ongoing clinical trials [16, 17].

In conclusion, retrospective studies in selected patients have demonstrated survival benefit for men receiving CRP or RT of the primary in M1 HSPC. Recently reported sub-group analyses from randomized, prospective data should be interpreted carefully in the context of current and evolving systemic therapies, inherent inadequacy of volume-based disease classification, and an underpowered and somewhat premature analysis of the sub group data. Taking all of this into consideration, there is currently not enough evidence to recommend RT to the primary as SOC for patients treated with ADT+abiraterone or ADT docetaxel, for low volume M1 HSPC. Additionally, given the negative findings overall for both HORRAD and STAMPEDE arm H, patients with high volume M1 HSPC should not receive local therapy outside of a clinical trial unless strictly palliative in nature. The field is in need of biologic classifiers to more appropriately categorize and treat men with therapies specific to the inherent biologic vulnerabilities of their disease.