Novel insights in the definition and treatment of high risk and oligometastatic prostate cancer

There is an urgent need to develop novel treatment strategies in the management of high-risk prostate cancer. These patients have a significantly elevated risk of disease recurrence and progression resulting in worse prognosis. To this end, the first objective of this thesis was to investigate the efficacy and tolerability of a novel second-line anti-androgen, apalutamide, prior to radical prostatectomy in high-risk PCa patients. The execution of the double-blind, placebo-controlled, randomized trial, ARNEO was the main task of this PhD project (Chapter 3). ARNEO is the first trial demonstrating that the addition of neoadjuvant apalutamide to conventional castration therapy results in significantly better pathological response compared with conventional castration therapy alone. However, it is yet unclear if these improved pathological outcomes will result in improved oncological outcome. Interestingly, we demonstrated that PSMA PET based imaging might be used to assess and predict local response during neoadjuvant hormonal treatment. Moreover, we observed that PTEN loss on prostate biopsy was associated with poor pathological response (in terms of minimal residual disease and residual cancer burden) to neoadjuvant hormonal therapy.

Despite local therapy, 27-53% of the prostate cancer patients develops PSA relapse. Currently, PSMA PET/CT is the standard of care in patients with BCR. The second objective of this thesis was to investigate the recurrence pattern of men with PSA failure following local therapy assessed with PSMA PET based imaging techniques and the therapeutic impact of PSMA PET based imaging. Knowledge of site-specific relapse in patients with PSA failure after local therapy may be of interest in order to guide further treatment and optimize the extent of salvage therapies such as salvage radiotherapy or salvage lymph node dissection. Further, it could help clinicians to counsel patients on their chances of being still eligible for MDT. Both in chapter 4 and 5  we observed that most patients (approximately 90%) develop oligometastatic recurrence (≤3 lesions) when assessed with PSMA PET based imaging at time of PSA relapse following local therapy. Consequently, most of these patients with biochemical recurrence are eligible for metastasis-directed therapy. Moreover, in chapter 4 we demonstrated that PSMA PET/MRI has a major impact on the therapeutic management in approximately one out of three patients. In chapter 5, we demonstrated that post-prostatectomy treatments (adjuvant/salvage hormonal therapy and/or radiotherapy) and the postoperative radiation field (prostate bed vs prostate bed plus pelvic lymph nodes) appear to have a significant impact on recurrence patterns. Patients who received postoperative hormonal therapy and radiotherapy more often had recurrence outside the pelvis compared to patients who did not receive any postoperative treatment. This knowledge can help clinicians to counsel patients on their chances on having locoregional recurrence and as such being eligible for locoregional metastasis-directed therapy.

As demonstrated in chapter 4 and 5, more prostate cancer patients are now diagnosed with a limited a number of lesions (oligometastatic recurrence) with the introduction of PSMA PET/CT at time of PSA relapse, creating a window of opportunity for metastasis-directed therapy. The aim of metastasis-directed therapy is to delay the initiation of salvage androgen deprivation therapy and to preserve the quality of life. Few prospective studies showed that metastasis-directed therapy could indeed delay initiation of systemic treatment and clinical progression. However, long-term outcome data are currently lacking and most prospective studies used radiotherapy-based metastasis-directed therapy (mostly stereotactic body radiotherapy). In contrast, the role of surgery-based metastasis-directed therapy (metastasectomy / salvage lymph node dissection) is less clear. Our tertiary referral center has a long experience in treating oligorecurrent prostate cancer patients with metastasis-directed therapy. The third objective of this thesis was to investigate the toxicity and oncological outcomes of oligorecurrent prostate cancer patients treated with metastasis-directed therapy at our tertiary referral center. In chapter 6, we reported the first feasibility series for visceral and skeletal surgical metastasis-directed therapy showing that the procedure is applicable and safe in selected subjects with oligometastatic prostate cancer. The promising PSA response after surgical metastasis-directed therapy, the long metastatic recurrence-free period and the oligometastatic recurrence pattern support the idea that these patients are affected by metastatic recurrence with less-aggressive biology. However, the survival impact of such approach remains a research question and should be addressed in future randomized controlled trials. In chapter 7, we demonstrated that robotic salvage lymph node dissection appears to be a safe alternative for the open procedure with the associated benefits of minimally invasive surgery, including shorter length of stay, lower estimated blood loss, and lower postoperative complication rates. No difference in early biochemical recurrence- and clinical recurrence-free survival was seen between both groups. Limitations of this study are its retrospective nature and the relatively small population. In chapter 8, we demonstrated that (repeated) metastasis-directed therapy is promising in terms of androgen deprivation therapy-free and castration-resistant prostate cancer-free survival for patients with oligorecurrent prostate cancer. However, these findings should be confirmed in prospective randomized controlled trials.

Today patients with biochemical recurrence without evidence of metastases are commonly observed until visible lesions occur or receive castration therapy in case of rapidly rising PSA. However, at very low PSA levels, even next generation imaging techniques such as PSMA PET/CT are often not powerful enough to detect clinical recurrence. Assuming that rapidly rising PSA following maximal local therapy with negative imaging is caused by micrometastasic disease confined to the bone, Radium-223 provides interesting therapeutic opportunities. Radium223 dichloride (Xofigo®) is an alpha-emitter which has similar molecular characteristics as calcium and binds to hydroxyapatite in newly formed bone. Following intravenous injection, it selectively accumulates into areas of increased bone remodelling such as osteoblastic bone metastases, emitting high-energy, short-range (<100µm) alpha particles. These alpha particles induce double-stranded DNA breaks in prostate cancer cells and the tissue microenvironment (osteoblasts, osteoclasts,…) resulting in a localised cytotoxic effect. The fourth objective of this thesis was to investigate whether the use of Radium-223 in men with BCR following maximal local therapy and without metastases on PSMA PET/CT might be curative or at least delay further progression by destroying micrometastases located in the bone. In a small prospective single-center study, we demonstrated that the use Radium-223 is safe in patients with PSA progression following maximal local treatment without detectable lesions on PSMA PET/CT and whole body MRI (chapter 9). However, the clinical benefit of Radium-223 in this setting is doubtful as significant oncological benefit is lacking. Improved patient selection by identifying patients who develop isolated skeletal recurrence might provide better oncological outcomes. 

In conclusion, this thesis project has provided useful insights in the therapeutic management of high-risk and oligometastatic PCa patients. Our findings might help to guide further research in these patient populations.