In developing and developed countries, the age-adjusted incidence of prostate cancer has risen with time (1). Currently, between 4 and 8% of North American men diagnosed with prostate cancer present with de novo metastatic disease (2), and approximately 10–15% develop distant metastases after local therapy with curative intent (3). Hence, there is a significant number of prostate cancer patients who ultimately will die of metastatic disease.

The contemporary standard of care for metastatic castration-sensitive prostate cancer (mCSPC) comprises androgen deprivation therapy (ADT) combined with either second generation androgen receptor signaling inhibitors (ARSIs) such as Abiraterone (ABI) (4, 5), Enzalutamide (6, 7) or Apalutamide (8), or with Docetaxel (DOC) chemotherapy (9–11). Moreover, local radiotherapy prolongs overall survival (OS) in low volume mCSPC (12, 13). Numerically, all of these interventions improved median overall survival (OS) in a clinically meaningful way compared to ADT alone with hazard ratios (HRs) between 0.61 and 0.88 (14). With the availability of such a broad therapeutic arsenal consisting of agents with different toxicity profiles, clinicians can choose the most suitable treatment option depending on associated comorbidities and burden as well as distribution of disease (15, 16).

Nonetheless, the rapid therapeutic advances over the last few years have also created challenges. First of all, there is no definite data on the comparative efficacy of the varied treatment modalities. While an opportunistic comparison of men recruited simultaneously for the ADT + ABI and ADT + DOC arms of the STAMPEDE trial (arms G and C, respectively) suggests a similar OS benefit, ARSIs appear to be the preferred treatment option in meta-analyses compared to DOC when applying surface under the cumulative ranking analysis (17–19). On the other hand, it is worth noting that DOC is more cost-effective than ABI (20–22). Secondly, there are no validated predictive (bio)markers of response to ARSIs or DOC (23). Thirdly, the clinical studies differed with respect to the eligibility criteria used, resulting in study cohorts with varying risk profiles, be it related to high versus low volume disease as defined in the CHAARTED study, high risk disease as outlined in the LATITUDE trial, or recurrent versus de novo mCSPC (4, 9, 24). As for the CHAARTED high volume and LATITUDE high risk definitions, they are in excellent but not perfect agreement, and both predict worse outcome (25–27). Finally, numerous prostate-specific antigen (PSA) based response parameters are associated with oncological outcome [e.g., absolute PSA nadir of ≤0.2 ng/ml, ≥50 or ≥90% PSA response (PSA50 and PSA90, respectively), and median time to PSA nadir], but they are not helpful for the initial treatment decision between DOC and ARSIs (28–30).

Based on the above, we decided to study the performance of ABI and DOC under real-world conditions when added to ADT for the treatment of mCSPC to compare the oncological activity of these drugs and to identify predictive markers of response.

In our retrospective single-center cohort study, we found mCSPC patients treated with DOC to be younger, having less comorbidities, and experiencing shorter PFS compared to men undergoing ABI therapy. Similarly, the time to first line systemic therapy for CRPC was shorter in the DOC group. Since PFS and the diagnosis of CRPC were triggered by biochemical progression in the majority of patients, it is not unexpected that these outcome measures were favored by ABI over DOC, owing to the androgen synthesis inhibitory activity of ABI. However, there was no significant difference in OS between the two treatment modalities. As such our population-based results confirm the findings of the opportunistic comparison between the DOC and ABI arms of the STAMPEDE trial (arms C and G, respectively) (17).

Our study also documents the feasibility and effectiveness of both DOC and ABI under real-world conditions. In fact, 93.7% of our patients completed six cycles of DOC, and only approximately 5% of patients stopped either DOC or ABI because of adverse effects. With respect to DOC effectiveness, our DOC cohort was comparable to the CHAARTED population of men undergoing chemohormonal therapy regarding median age (65.76 versus 64 years) and rate of high volume disease (68.35 versus 66.2%), de novo metastatic presentation (65.82 versus 72.8%), visceral metastasis (20.25 versus 14.4%), and Gleason score 7 or higher disease (94.4 versus 94.1%) (24). The median OS was 57.6 months in CHAARTED and 57.5 months in our group of patients after a median follow-up of 39.6 months. Furthermore, the median time to CRPC was 18.6 (95%CI 12.6–25.1) and 20.2 (17.2–23.6) months in our cohort versus the experimental arm of CHAARTED, respectively (24). On the contrary, Lavoie et al. described inferior outcomes in their population-based series of 156 patients compared to our findings (33). However, their rate of high-volume disease was higher (79.5 versus 68.35%); fewer patients finished six cycles of DOC (81 versus 93.7%), and more men discontinued DOC because of toxicities (10 versus 5%).

With respect to ABI, our cohort was older compared to LATITUDE AND STAMPEDE-G, and situated between these two clinical trial populations in terms of risk factors such as LATITUDE high-risk and CHAARTED high-volume disease, de novo presentation, and rate of visceral metastasis. Although the relatively short median follow-up of 25.1 months of our patients precludes a definite comparison with LATITUDE and STAMPEDE-G, it is reassuring that 80.4% of our patients were alive at 2 years.

For the identification of predictive factors of clinical benefit, we focused on PFS as the primary endpoint in the entire study cohort. LATITUDE low-risk disease, achieving a PSA90 at 3 months, and older age at diagnosis of mCSPC were found to be independently associated with longer PFS. Interestingly, CHAARTED low-volume disease at baseline did not result in prolonged PFS in multivariable analysis. The LATITUDE risk definition might have better predictive potential because it incorporates not only tumor burden but also de novo presentation as factors of worse outcome (34). Deep PSA responses have been associated with superior outcome in men undergoing chemohormonal therapy or ABI combined with ADT for mCSPC (28, 30). Similarly, in our cohort PSA90 at 3 months was an independent predictor of superior PFS. With longer follow-up, we will be able to use our dataset for a predictive factor analysis using OS as the primary endpoint.

In the future, predictive clinical parameters such as the ones identified in our analysis might be used in conjunction with emerging molecular markers for therapeutic decisions. SPOP mutations appear to identify a group of mCPSC patients with excellent response to ADT alone (35). Conversely, Harshman et al. showed that elevated IL-8 levels predict shorter time to CRPC and OS independent of DOC administration, tumor burden, and recurrent versus de novo metastatic presentation, using baseline serum samples from CHAARTED (36). Luminal B subtype mCSPC was found to be associated with superior OS in men undergoing chemohormonal therapy compared to ADT alone, whereas men with basal subtype did not benefit from adding DOC (37). Combining ADT with apalutamide (and potentially other ARSIs) might be particularly needed in mCSPC with a high DECIPHER® genomic classifier score, low androgen receptor activity, and/or basal phenotype (38). The presence of germline DNA damage repair alterations predicts early progression from de novo mCSPC to mCRPC, yet such patients might be amenable to treatment with poly (ADP-ribose) polymerase inhibitors (39). Finally, deep tumor sequencing is expected to aid further in the precise molecular classification of mCSPC for therapeutic decision making (40–42).

Some limitations regarding our analyses are worth mentioning, including the retrospective data collection and limited sample size. Furthermore, the single institution nature of our study could affect the external validation of our findings, as could differences between the treatment cohorts in terms of age, comorbidities and time of follow-up among others. Regarding the latter, the relatively short median follow-up in the ABI arm is explained by the only recent availability in Canada of ABI for mCSPC. Furthermore, imaging was timed according to treating physicians’ discretion, which could impact the assessment of PFS.

To sum up, the findings presented herein support the feasibility and effectiveness of combining DOC or ABI with ADT for men with mCSPC under real-world conditions. The presence of high-risk mCSPC as per LATITUDE criteria, lack of a PSA90 at 3 months, and younger age at diagnosis of mCPSC predict shorter PFS and as such may identify a cohort of patients in need for further refinement of the initial management.

The raw, de-identification data supporting the conclusions of this article will be made available by the authors without undue reservation.

The studies involving human participants were reviewed and approved by the Research Ethics Board of Sunnybrook Research Institute. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JB and UE conceived and designed the study. JB, MK, and AS collected and assembled the data. LZ performed the statistical analysis. JB, MS, and UE analyzed and interpreted the data. JB and UE wrote the manuscript. All authors contributed to the article and approved the submitted version.

This study was made possible by support from the Joseph and Silvana Melara Cancer Research Fund (Toronto, ON, Canada) to UE.

UE has received honoraria from Janssen Inc. Canada for consulting and educational activities.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.