Recurrent prostate adenocarcinoma after radical prostatectomy: Principles of multidisciplinary management across a spectrum of disease

Short abstract

A case vignette is presented of a patient with recurrent prostate cancer after radical prostatectomy, covering the spectrum from biochemical recurrence to metastatic disease. The patient provides his insight into this journey as he is treated on serial clinical trials as the disease recurs.

CASE OVERVIEW

A man aged 76 years in good health presented for evaluation of a rising prostate‐specific antigen (PSA) level after prior radical prostatectomy (Figure 1). Briefly, his prostate cancer had been diagnosed 5 years prior in the setting of a rising PSA. A standard biopsy had revealed International Society of Urological Pathology (ISUP) grade group 3 disease, and he underwent radical prostatectomy without pelvic nodal sampling. Pathologic examination demonstrated extracapsular extension and the presence of intraductal carcinoma; otherwise, at final pathology, the tumor was ISUP grade group 3, with negative surgical margins but evidence of perineural invasion. Postoperative PSA was undetectable for 3 years and then began to slowly rise, reaching 0.06 ng/dL 42 months after surgery. PSA then began to rise more rapidly, reaching 0.37 ng/dL 51 months after surgery. He underwent a prostate‐specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan at that time, which showed an enhancing nodular soft tissue along the right prostate bed (1.1 × 0.5 cm) with intense PSMA uptake, as well as uptake in a 3‐mm right internal iliac node, a 3‐mm right common iliac node, and a 3‐mm aortocaval node (Figure 2). Focal uptake in a left presacral area was thought to represent a ganglion, whereas uptake in the T11 vertebral body was equivocal; follow‐up magnetic resonance imaging (MRI) of the thoracic spine confirmed that the T11 lesion was a hemangioma. MRI of the prostate bed showed a small focus of T2‐hypointense soft tissue in the right pelvis lateral to the prostatectomy bed measuring 15 × 5 mm.

FIGURE 1.

Treatment course after radical prostatectomy. Timeline of the patient’s clinical course, starting from radical prostatectomy. Time 0 indicates the date of surgery. Follow‐up is indicated months. PET/CT indicates positron‐emission tomography/computed tomography; NCT, ClinicalTrials.gov identifier; PSA, prostate‐specific antigen; PSMA, prostate‐specific membrane antigen; SBRT, stereotactic body radiotherapy.

FIGURE 2.

Initial PSMA PET/CT scan showing (from top to bottom) positive lesions in T11, an aortocaval node, a right common iliac node, a right internal iliac node, and the prostate bed. The T11 lesion was identified as a hemangioma on a subsequent MRI. MRI indicates magnetic resonance imaging; PET/CT, positron‐emission tomography/computed tomography; PSMA, prostate‐specific membrane antigen.

The patient was evaluated by a radiation oncologist, urologist, and medical oncologist, and decided to pursue a clinical trial of stereotactic body radiotherapy (SBRT; ClinicalTrials.gov identifier NCT03541850). ¹ He received 40 grays (Gy) in five fractions to the prostate bed gross nodule and PSMA‐positive nodes, 30 Gy in five fractions to the prostate bed, and 25 Gy in five fractions to the elective lymph node regions. In addition to SBRT, he started a planned short course of androgen‐deprivation therapy (ADT; this was allowed on the protocol) but stopped after 1 month because of intolerance. PSA dropped to 0.18 ng/dL 6 months after SBRT, but then rose to 0.27 ng/dL 3months later and 0.99 ng/dL 6 months after that (now nearly 6 years after his prostatectomy). PSMA PET/CT imaging revealed a decrease in size and positivity of the right internal iliac node, with stable low uptake in the right CI node and prostate bed, and resolution of the aortocaval node. However, there was new uptake in two 4–6 mm left para‐aortic nodes and a 5‐mm node anterior to the aorta (Figure 3).

FIGURE 3.

PSMA PET/CT at second recurrence, showing (top) lesions in a node anterior to the aorta and (bottom) two para‐aortic nodes. PET/CT indicates positron‐emission tomography/computed tomography; PSMA, prostate‐specific membrane antigen.

The patient enrolled on a trial of PSMA PET/CT–guided, metastasis‐directed therapy (MDT) with 6 months of androgen‐annihilation therapy (AAT; leuprolide, apalutamide, and abiraterone; ClinicalTrials.gov identifier NCT03902951). ² The highest PSA before beginning AAT was 1.1 ng/dL. He received 1 month of AAT, then completed SBRT to the PSMA‐positive para‐aortic nodes (30 Gy in five fractions). His PSA decreased to 0.02 ng/dL after 6 months of AAT. Within 1 month of cessation, his testosterone had recovered to 312 ng/dL, and his PSA rose slightly, to 0.05 ng/dL. It remained <0.1 ng/dL for 9 months, then increased to 0.22 ng/dL nearly 12 months after testosterone recovery (92 months after prostatectomy).

A PSMA PET/CT was obtained, which showed two new PSMA‐positive lesions in left para‐aortic nodes as well as increasing uptake in the right prostatectomy bed (adjacent to his prior treatment area; Figure 4). MRI of the prostate bed showed a small, T2‐hypointense, soft tissue, nodular focus in the right pelvis lateral to the prostatectomy bed measuring approximately 9 × 9 mm, with delayed enhancement. PSA rose to 0.45 ng/dL in 2 months, and he enrolled in a randomized clinical trial evaluating PFS using PSMA‐guided SBRT with or without two cycles of the PSMA‐radioligand 177LuPNT2002 (ClinicalTrials.gov identifier NCT05496959). ³ The patient was assigned to the intervention arm; and, after treatment (including SBRT to the prostate bed recurrence and PSMA‐positive para‐aortic nodes), his PSA dropped to 0.02 ng/dL at 3 months and became undetectable after 6 months. Serial PET/CT scans obtained 12 and 24 months later remain negative, and his PSA remains undetectable through the present, now 10.5 years after his radical prostatectomy.

FIGURE 4.

PSMA PET/CT at third recurrence, showing (top, middle) lesions in two para‐aortic nodes and (bottom) an increase in positivity in the right prostatectomy bed lesion that was previously treated. PET/CT indicates positron‐emission tomography/computed tomography; PSMA, prostate‐specific membrane antigen.

FIRST BIOCHEMICAL RECURRENCE

Timing of postoperative radiotherapy

Radiation oncology and urology perspective

Secondary radiotherapy (also called salvage therapy) for recurrent prostate cancer after radical prostatectomy is a standard‐of‐care, curative intervention. ⁴ , ⁵ Traditionally, the definition of biochemical recurrence after prostatectomy has been a serum PSA level ≥0.2 ng/mL, confirmed on a confirmatory laboratory test. Multiple studies suggest that early secondary radiotherapy in the setting of recurrence—i.e., delivered at a PSA level ≤0.5 ng/mL—is associated with improved outcomes compared with late secondary radiotherapy, with the pre‐radiotherapy PSA level established as a significant prognostic biomarker. ⁶ , ⁷ Adjuvant radiotherapy—defined as the delivery of radiation to the prostate fossa with or without pelvic lymph nodes purely based on the presence of aggressive disease factors on pathologic analysis and without any evidence of recurrence (i.e., with an undetectable PSA level)—has been shown to improve biochemical relapse in several randomized trials, but only the oldest of these, which did not have a rigorous approach to secondary radiotherapy in the control arm, demonstrated an overall survival benefit. ⁸ , ⁹ , ¹⁰ , ¹¹ Given concerns of potential overtreatment with an adjuvant approach, three randomized trials were run comparing adjuvant radiotherapy versus early secondary radiotherapy (i.e., at a PSA level ≤0.5 ng/mL). Individually, no trial identified a robust benefit from adjuvant radiotherapy, although the adjuvant approach was associated with increased morbidity. ¹² , ¹³ , ¹⁴ The ARTISTIC meta‐analysis included trial‐level data from these three trials, with the goal of comparing event‐free survival after adjuvant versus early secondary therapy. ¹⁵ That analysis demonstrated no difference in event‐free survival between these approaches, suggesting that early secondary therapy is sufficient for the majority of patients who are considering postoperative therapy. Notably, these trials included proportionately few patients (<20%) with very aggressive features (e.g., seminal vesicle invasion or ISUP grade 4–5 disease). To that end, a large, retrospective, tri‐institutional series evaluating 2424 men who had adverse pathologic features identified at radical prostatectomy indicated an all‐cause mortality benefit from adjuvant versus early secondary radiotherapy. ¹⁶

Nuclear medicine perspective

The traditional radiotherapy target volume includes only the prostatic fossa with or without pelvic lymph nodes. However, a rising PSA could be from prostate cancer cells in any location. In most solid organ cancers, postoperative radiotherapy is typically delivered in the adjuvant setting on the basis of pathologic risk factors. Despite concerns about systemic occult disease for a patient who has prostate cancer with a rising PSA after radical prostatectomy, the data discussed above that support early secondary radiation coupled with the potential morbidity of radiation have led to great interest in the incorporation of advanced imaging techniques to refine the design of postoperative radiotherapy fields. Specifically, it may allow the identification of patients in whom prostatic fossa–directed radiation may be futile and/or insufficient due to spread of the disease outside this area. Acceptable imaging techniques available for staging in the recurrent setting were technetium‐99 bone scan, CT, and MRI, none of which have sufficiently high sensitivity or specificity, particularly in the context of a PSA <2 ng/mL. ⁵ Advanced molecular imaging with and fluciclovine PET and PSMA‐based tracers has been shown to dramatically improve sensitivity in this setting. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² Detailed topographical analyses of recurrence patterns suggests that a fair number of patients who present for secondary radiotherapy actually have disease outside a traditional postoperative radiotherapy field. ²³

Several randomized trials have investigated the potential benefit of using imaging data from PET scans to guide field design. The EMPIRE‐1 trial enrolled men who were planning to undergo secondary radiotherapy for a rising PSA after radical prostatectomy and randomized them to either receive conventional imaging (e.g., CT and bone scan) versus conventional imaging with a fluorine 18 (¹⁸F)‐fluciclovine PET/CT scan to assist with radiotherapy planning. ²⁴ Notably, the findings on the ¹⁸F‐fluciclovine PET/CT could be used to expand the radiotherapy target volume (e.g., by adding pelvic lymph node radiation if nodes were positive), but increasing the dose to macroscopic disease seen only on ¹⁸F‐fluciclovine PET/CT was not allowed. The primary outcome was failure‐free survival, which was improved from 63% to 75.5% with the incorporation of ¹⁸F‐fluciclovine PET/CT. The PSMA iSRT trial enrolled a similar population (men planning to undergo secondary radiotherapy) and randomized them to receive either conventional imaging (e.g., CT and bone scans) versus conventional imaging with an ¹⁸F‐DCFPyL‐PSMA PET/CT scan to assist with radiotherapy planning. ²⁵ The primary outcome was failure‐free survival, which was significantly improved (hazard ratio [HR], 0.50; p = .04).

With regard to the optimal tracer, fluciclovine and PSMA have not been directly compared in a phase 3 randomized trial. The EMPIRE‐2 trial randomized men planning to undergo secondary radiotherapy to receive either an ¹⁸F‐fluciclovine PET/CT or a gallium 68 (⁶⁸Ga)‐PSMA PET/CT. ²⁶ Unlike EMPIRE‐1, the EMPIRE‐2 trial allowed intensification of the radiation dose to disease seen on PET/CT scanning, thus the primary outcome of the trial was 2‐year event‐free survival using the treatment arm of EMPIRE‐1 as its comparator (i.e., EMPIRE‐2 was not designed to compare its two arms against each other but, instead, to compare the overall 2‐year event‐free survival in both arms against that from the ¹⁸F‐fluciclovine arm of EMPIRE‐1). Two‐year event‐free survival was similar between randomized arms (87% vs. 88%; p > .9), whereas the overall EMPIRE‐2 strategy demonstrated improved event‐free survival compared with EMPIRE‐1 (after propensity score weighting, 84% in EMPIRE‐2 vs. 73% in EMPIRE‐1; p = .01). A prospective, albeit nonrandomized, trial directly compared scan positivity rates. ²⁷ In that trial, men with PSA levels between 0.2 and 2 ng/mL who were planning to undergo secondary radiotherapy underwent both an ¹⁸F‐fluciclovine PET/CT scan and a ⁶⁸Ga‐PSMA PET/CT. ⁶⁸Ga‐PSMA PET/CT had a significantly greater detection rate (56% vs. 26%; p = .0026). ²⁷ The largest trial, the PSMA SRT trial (ClinicalTrials.gov identifier NCT03582774), randomized men planning to undergo secondary radiotherapy to receive either conventional imaging or a ⁶⁸Ga‐PSMA PET/CT plus conventional imaging before secondary radiotherapy. The primary end point is the success rate of secondary radiotherapy at 5 years, defined by PSA response. This trial has not yet reported its primary outcome.

One topical question is whether secondary radiotherapy can be omitted if an advanced molecular scan demonstrates no evidence of gross disease. Although PET imaging does greatly improve sensitivity, the sensitivity is still not perfect, and the absence of disease on a PET/CT does not equate to the absence of disease in the prostate fossa. Indeed, two large, retrospective series have found that the failure‐free survival rate appears to be highest in patients with a negative PSMA PET/CT who receive secondary radiotherapy. ²⁸ , ²⁹ The ongoing DIPPER trial is investigating the impact of omitting secondary radiotherapy in the setting of a negative PSMA PET/CT. ³⁰ In that trial, men with a PSA of 0.2–0.5 ng/mL after prior radical prostatectomy who have no visible disease on a PSMA PET/CT scan are randomized to secondary radiotherapy or surveillance. The primary end point is 3‐year event‐free survival, with events defined as any of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiologic evidence of metastatic disease, or initiation of any therapy. In total, these data support the use of advanced molecular imaging, particularly with PSMA PET/CT, to guide radiation field design, with a plan to deliver radiation in the absence of visualized disease on these scans.

The role of hormone therapy: Multidisciplinary perspective

When postoperative radiotherapy is delivered, several intensification strategies can be considered, including the addition and prolongation of concurrent hormone therapy, elective lymph node radiation, and dose escalation to the prostate bed. Adding and prolonging hormone therapy with definitive radiotherapy has been shown to improve outcomes in men with localized prostate cancer compared with radiotherapy alone. ³¹ Its benefit in the postoperative setting is less clear, with six randomized trials reaching different conclusion. ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ Understanding the actual benefit of adding and/or prolonging hormone therapy is critical because hormone therapy can significantly affect quality of life. ³⁹ The POSEIDON individual patient data meta‐analysis included data for 6057 patients enrolled across these six randomized comparisons and was designed to evaluate the overall survival benefit of adding hormone therapy to postoperative radiotherapy. ⁴⁰ The results suggested that the addition of hormone therapy only improved overall survival in men who had a PSA level >0.5 ng/mL at the time of postoperative radiotherapy. Furthermore, there was no evidence of a benefit in prolonging hormone therapy beyond a short duration (4–6 months). The discrepancy with the definitive radiotherapy setting could be cause hormone therapy is a known radiosensitizer ⁴¹ and, in the postoperative setting with low PSAs, the burden of disease may not be high enough for this radiosensitization to improve outcomes. This is consistent with the overall negative results of dose‐escalation studies in the context of secondary radiotherapy, although emerging data suggest that patients whose tumors exhibit transcriptomic evidence of response to radiation may benefit. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ Alternatively, the primary benefit of hormone therapy at high PSA levels may simply be from suppressing occult systemic disease. Emerging data suggest that biomarkers like the Decipher genomic classifier (which is a score based on the expression of 22 genes that can be derived from a microarray analysis of a prostatectomy specimen) may play a role in identifying patients most likely to benefit from hormone therapy. ⁴⁶ The randomized phase 2 NRG GU‐006 trial (ClinicalTrials.gov identifier NCT03371719) enrolled men with PSA between 0.1 and 1.0 ng/mL after radical prostatectomy and randomized them to receive 6 months of apalutamide, a second‐generation androgen receptor antagonist, or placebo with secondary radiotherapy. ⁴⁷ , ⁴⁸ Patients were stratified based on having a transcriptomic classification of luminal B versus non–luminal B disease based on the PAM50 classifier, which has been studied extensively in breast cancer and is thought to predict for response to hormonal axis manipulation in both prostate and breast cancer.⁴⁷ The primary end point was biochemical progression‐free survival, and the trial was designed to test the benefit of apalutamide over placebo in the luminal B subtype group, then in the non‐luminal B subtype group. In the luminal B group, apalutamide significantly improved biochemical progression‐free survival (HR, 0.45; p = .0062); whereas, in the non‐luminal B group, it did not (HR, 0.95; p = .44).

Postoperative radiotherapy fractionation: Radiation oncology perspective

With regard to radiotherapy regimen, conventionally fractionated radiotherapy (1.8–2.0 Gy per fraction) remains the standard of care for postoperative radiotherapy. ⁵ The NRG GU‐003 trial enrolled men who presented for postoperative therapy and randomized them to either 66.6 Gy in 37 fractions (conventional fractionation) or 62.5 Gy in 25 fractions (moderate hypofractionation). ⁴⁹ The trial was designed to demonstrate noninferiority with respect to the 2‐year change in patient‐reported bowel and urinary domains of the Expanded Prostate Cancer Composite Index. Noninferiority was ultimately demonstrated, with between‐arm mean change scores of 0.94 points for urinary function (a noninferiority margin of 6.0) and 2.76 points (a noninferiority margin of 10.0). However, some concern exists related to potential long‐term consequences from this type of regimen, which is intrinsically dose‐escalated, with one retrospective institutional series reporting a crude incidence of severe bowel or bladder toxicities of 27.3% after a median follow‐up of 13.5 years. ⁵⁰ Long‐term follow‐up from prospectively treated patients who received lower dose moderately hypofractionated radiotherapy (2.65 Gy per fraction to 52.5 Gy) are reassuring in this regard. ⁵¹ Given the favorable profile of SBRT in the setting of definitive radiotherapy, ⁵² , ⁵³ there has been interest in this approach for postoperative radiotherapy. The largest prospective experience to date comes from the SCIMITAR trial, on which the patient in this case was treated. This phase 2 trial enrolled 100 men at our institution between 2018 and 2021 who were presenting for postoperative radiotherapy and delivered SBRT to the prostate fossa with or without pelvic nodes with a prostate fossa dose of 30–34 Gy in five fractions. ⁵⁴ At 2 years of follow‐up, patient‐reported urinary and bowel quality‐of‐life outcomes were similar to those of a comparator cohort of patients receiving conventionally fractionated radiotherapy. ⁵⁵ With 4 years of minimum follow‐up, the biochemical recurrence‐free survival rate was 60%, with adverse event profiles that were quantitatively similar to those among patients who received longer course radiotherapy. ¹ Results from ongoing phase 2 trials (e.g., EXCALIBUR [ClinicalTrials.gov identifier NCT04915508] and MASAMUNE [ClinicalTrials.gov identifier NCT07077239]) will provide additional clarity, with SBRT now being a conditional option for postoperative radiotherapy in the National Comprehensive Cancer Network guidelines. ⁵ Nonetheless, it remains imperative to ensure that abbreviated fractionation schemes do not result in increased adverse events.

Systemic therapy alone in biochemically recurrent, nonmetastatic disease: Medical oncology perspective

One important question is the role of systemic therapy intensification in the setting of biochemically recurrent disease. The EMBARK trial enrolled men with biochemically recurrent disease who had a PSA doubling time ≤9 months and a PSA ≥1 ng/mL after radical prostatectomy or a PSA ≥2 ng/mL after definitive radiotherapy and randomized them to receive 36 weeks of ADT with leuprolide, 36 weeks of oral enzalutamide (a second‐generation androgen receptor inhibitor), or 36 weeks of both drugs together. ⁵⁶ , ⁵⁷

The primary end point, metastasis‐free survival, was improved by both enzalutamide monotherapy and combination therapy compared with leuprolide alone (HR, 0.63 [p = .005] and 0.42 [p < .001], respectively). ⁵⁶ A subsequent update indicated that overall survival also was improved in the combination therapy group versus the leuprolide monotherapy group (HR, 0.60; p < .001), but not in the enzalutamide monotherapy versus leuprolide monotherapy comparison (HR, 0.83; p = .19). ⁵⁷ Although the patient did not technically meet eligibility criteria for EMBARK, he did approach it at the time of his second recurrence (PSA 0.99 ng/mL), thus intermittent therapy with enzalutamide plus leuprolide, or potentially enzalutamide alone, was an option. Notably, however, patients enrolled on EMBARK did not have PSMA PET/CT data available. Analyses have indicated that ≥85% of patients who would have met criteria for enrollment in EMBARK, have detectable disease on PSMA PET‐CT, including close to one half of patients exhibiting metastatic disease despite no evidence of recurrence on conventional imaging. ⁵⁸ Intermittent hormone therapy may not have been appropriate for this patient, who did not tolerate even single‐agent ADT initially and only considered complying with a 6‐month duration at the time of his second recurrence. Indeed, tolerability and patient preference remain major determinants of whether intensification is feasible, regardless of what trial data support.

OLIGORECURRENT, HORMONE‐SENSITIVE PROSTATE CANCER

Overview and concept of metastasis‐directed therapy: Multidisciplinary perspective

Over the ensuing decades, there has been growing appreciation of oligometastatic prostate cancer as a distinct disease state characterized by the presence of a limited scope of metastases (typically less than five) on advanced imaging, with a unique biologic underpinning, rendering it distinct from polymetastatic disease that is simply detected early or with imaging of limited sensitivity. ⁵⁹ The synchronous development of noninvasive ablative approaches like SBRT has heralded broad interest in MDT using SBRT. The seminal phase 2 SABR‐COMET trial enrolled patients with a controlled primary tumor who had from one to five metastatic lesions to receive either palliative standard‐of‐care treatments or SBRT to all lesions. ⁶⁰ The primary end point was overall survival; at the time of the initial report (median follow‐up, 25 months), the addition of SBRT to standard‐of‐care treatment improved overall survival (HR, 0.57; p = .09). On long‐term follow‐up, 5‐year overall survival rates were 42.3% with SBRT and 17.7% with observation (p = .006). ⁶¹ Two smaller, randomized, phase 2 trials compared MDT with observation specifically in patients who had oligometastatic prostate cancer. The STOMP trial included men who had from one to three lesions on advanced choline PET/CT and primarily used SBRT for MDT, ⁶² whereas the ORIOLE trial included men who had from one to three lesions on conventional imaging and exclusively used SBRT for MDT; in both trials, the control arm was observation. ⁶³ The primary end point of STOMP was ADT‐free survival, whereas the primary end point of ORIOLE was progression at 6 months. Both trials, individually and in a subsequent pooled analysis, demonstrated that MDT was associated with improved progression‐free survival compared with observation (HR, 0.44; p < .001). ⁶⁴

The WOLVERINE meta‐analysis included individual patient data from 574 men enrolled across six randomized phase 2 trials in which patients with oligometastatic disease were randomly assigned to MDT plus standard of care versus standard of care alone. ⁶⁵ The analysis indicated that MDT was associated with significantly improved progression‐free survival (HR, 0.45; p < .0001), radiographic progression‐free survival (HR, 0.59; p < .0001), and castration‐resistance–free survival (HR, 0.58; p = .017). ⁶⁵ A numerical improvement in overall survival fell short of the threshold for statistical significance (HR, 0.64; p = .057). A large, pooled, retrospective study demonstrated that, among men receiving MDT without hormone therapy, the burden of disease (quantified by the number and extent of metastases, pre‐MDT PSA level, and PSA doubling time) may be a robust indicator of hormone therapy‐free survival. ⁶⁶

Hormone therapy in oligometastatic prostate cancer: Radiation oncology and medical oncology perspective

The interplay of hormone therapy with MDT merits further discussion. The randomized EXTEND basket trial enrolled men with oligometastatic prostate cancer and randomized them to either ADT alone or SBRT added to ADT; patients receiving intermittent and continuous ADT were in separate baskets. ⁶⁷ , ⁶⁸ The primary end point was progression‐free survival. The addition of MDT improved progression‐free survival in both the continuous ADT basket (HR, 0.50; p = .036) and the intermittent ADT basket (HR, 0.25; p < .001). It is noteworthy that, among patients receiving intermittent hormone therapy, the addition of MDT also improved eugonadal progression‐free survival or the progression‐free survival time after recovery of testosterone (HR, 0.32; p = .03). This is a critical end point because hormone therapy alone will suppress progression for the entirety of its duration—unless androgen‐independent disease emerges—and for a period afterward. With ADT specifically, this recovery period can be prolonged. ⁶⁹ Therefore, eugonadal progression‐free survival is a critical end point with regard to the appraisal of a true change in the disease’s natural history. A key trial in this context is the RADIOSA trial, which enrolled men with oligometastatic disease and randomized them to either SBRT to all sites alone or SBRT to all sites with 6 months of ADT. ⁷⁰ The primary outcome was clinical progression‐free survival, which was improved (HR, 0.43; p = .001). However, eugonadal progression‐free survival was not improved (HR not provided; p = .5), suggesting that the addition of ADT delayed but did not destroy occult metastases. ⁷¹ Other trials, such as DART (ClinicalTrials.gov identifier NCT04641078) and PROMOTHEAN (ClinicalTrials.gov identifier NCT05053152), are also investigating the benefit of adding hormone therapy to SBRT; early results from the DART trial suggest only a transient benefit from the addition of darolutamide to SBRT. ⁷²

The patient in the current case was treated on a single‐arm phase 2 trial, SATURN, in which PSMA PET/CT–guided MDT was integrated with 6 months of androgen annihilation therapy (AAT; leuprolide, apalutamide, and abiraterone). ² The rationale was that a combination of MDT and intense hormone therapy for a finite duration would optimize eugonadal progression‐free survival, with the proportion of patients who had an undetectable PSA level 6 months after testosterone recovery used as the primary end point. With a finite course of hormone therapy alone, even AAT, this proportion would be expected to be approximately 1%, whereas SBRT alone likely would not address any potentially occult disease. The trial enrolled 28 patients between 2021 and 2022, with 26 completing protocol therapy. Among these, 50% of patients had an undetectable PSA level 6 months after testosterone recovery, rendering the trial positive (p < .0001). ² However, 21% of patients had grade 3 or greater adverse events. Given other signals suggesting a lack of benefit for AAT over dual‐agent therapy, ⁷³ this specific approach with triplet therapy is unlikely to be investigated further in this context. Of note, in the SATURN trial, receipt of prior hormone therapy was a negative prognostic factor (i.e., patients with prior exposure to hormone therapy had a shorter eugonadal progression‐free survival). A subsequent pooled analysis with a similar trial in the context of de‐novo oligometastatic prostate cancer confirmed this finding. ⁷⁴ A potential explanation is that successive rounds of shorter duration hormone therapy ultimately may engender the development of more aggressive disease.

Radioligand therapy in oligorecurrent disease

An overall desire to optimize systemic control in patients who have oligometastatic disease while avoiding the morbidity of hormone therapy has led to the investigation of alternative intensification strategies. Radionuclide therapy with the alpha‐emitter and calcium mimetic radium 223 (²²³RaCl₂) has been shown to improve overall survival in metastatic castration‐resistant prostate cancer. ⁷⁵ Because prostate cancer metastases exhibit bone tropism, the addition of ²²³RaCl₂ to SBRT was anticipated to improve progression‐free survival in oligometastatic disease. The RAVENS trial enrolled patients who had oligometastatic prostate cancer and at least one bone lesion and randomized them to receive either SBRT to the metastases or SBRT to the metastases followed by four cycles of adjuvant ²²³RaCl₂, with a primary end point of progression‐free survival. ⁷⁶ Unfortunately, patients who received four cycles of adjuvant ²²³RaCl₂ after SBRT had numerically worse progression‐free survival (adjusted HR, 1.42; p = .24).

PSMA‐based radioligand therapy has also been shown to improve survival compared with standard‐of‐care systemic therapy in metastatic castration‐resistant prostate cancer. ⁷⁷ , ⁷⁸ , ⁷⁹ In these settings, patients often have widely metastatic disease, with large, bulky tumors and few therapeutic options remaining. The challenge in the oligometastatic disease state is different and relates to the presence of occult microscopic disease that is not visible. The randomized phase 2 LUNAR trial investigated the hypothesis that the addition of lutetium 177 (¹⁷⁷Lu)‐PNT2002 to SBRT in this context would improve survival outcomes over SBRT alone by action on occult disease. ³ That trial enrolled men with oligometastatic prostate cancer and randomized them to either SBRT alone or two cycles of neoadjuvant ¹⁷⁷Lu‐PNT2002 followed by SBRT, with a primary outcome of progression‐free survival. With a median follow‐up of 22 months, it was demonstrated that the addition of ¹⁷⁷Lu‐PNT2002 significantly improved progression‐free survival (from a median of 7.4 to 17.6 months; HR, 0.37; p < .0001). The current patient was enrolled on the LUNAR trial and was treated on the investigational arm; he remains disease‐free to this date.

Notably, 98% of progression events were defined by new lesions on PSMA PET/CT, underscoring that the mechanism of action was through impact on microscopic disease. The phase 3, randomized PSMA‐DC trial (ClinicalTrials.gov identifier NCT05939414) is investigating whether four cycles of adjuvant ¹⁷⁷Lu‐PSMA‐617, a similar radioligand therapy, improves metastasis‐free survival over SBRT alone. Notably, the majority of patients in the LUNAR trial, even those on the investigational arm, experienced progression, underlining that treatment could be further optimized. One approach would be to use alpha‐emitting PSMA radioligand therapy, such as actinium 225‐PSMA‐617; this approach is being actively studied in the phase 2, randomized ANDROMEDA trial (ClinicalTrials.gov identifier NCT07150715). Regardless of the specific radioligand therapy used, it will be imperative to appropriately assess the potential long‐term adverse effects of these agents in patients with a long life expectancy, particularly with respect to serious consequences such as clonal hematopoiesis of indeterminate potential. ⁸⁰

Overall, MDT, particularly using SBRT, remains an important intervention for patients who have oligometastatic prostate cancer based on multiple phase 2, randomized trials and an individual patient data meta‐analysis largely based on patients with oligorecurrent disease, as outlined above. Whether the addition of SBRT to standard‐of‐care systemic therapy improves castration resistance—free survival or overall survival in a broader population that includes patients with synchronous, de‐novo oligometastatic disease is the subject of multiple ongoing phase 3 trials, including STAMPEDE 2 (ClinicalTrials.gov identifier NCT06320067), OLIGO‐PRESTO (ClinicalTrials.gov identifier NCT04115007), and VA STARPORT (ClinicalTrials.gov identifier NCT04787744).

PATIENT PERSPECTIVE

I first heard of PSA from my cardiologist. Ever since I had open‐heart surgery for a mitral valve replacement, my cardiologist recommended checking blood often, and he made sure I had a PSA checked each year. My PSA eventually rose from a normal level 1 year to above 6.45 ng/mL the next. I was referred to a urologist who did a biopsy. It showed cancer in three spots. I then searched for a doctor that had experience in robotic prostate surgery. I ultimately decided on an experienced surgical team near my home. The day after the surgery, the urologist called me and told me that he didn’t think they got all of the cancer; and, in a few years when my PSA level starts to get higher, they would need to start me on hormone treatments. I didn’t feel like I got treated very well, and I started looking for alternatives. Meanwhile, my PSA unfortunately did start to rise, like predicted.

My cardiologist referred me to another urologist, who told me he was going to retire soon and that he had been reading about what he thought would be a breakthrough in prostate cancer treatment, the PSMA scan. He said the treatment has not been approved yet but thought I should check it out. He said they had a new scan machine at UCLA and a hospital in San Francisco. He said he would write a letter to UCLA to see if they would take me as a patient.

Soon, I was able to meet Dr Kishan and his team at UCLA. I learned that, unfortunately, the PSMA scan would not be covered by Medicare or my supplemental insurance because it was not approved. However, it was available on a clinical trial, which I decided to participate in. As it turns out, it saved my life. The scan showed something in the prostate bed and two lymph nodes. For me, a long course of radiation would have been logistically challenging. Dr Kishan enrolled me in his trial of a course of 5 days of radiation (SBRT) using advanced technology. I’ve always been interested in cutting‐edge treatments, and the idea of a trial appealed to me.

My PSA went down initially after radiation, but unfortunately, by about 18 months later, my PSA was back up, now at 1.1 in October 2021. I had another PSMA scan and it showed two new nodes. I was offered the SATURN trial, which involved intense hormone therapy (Lupron plus two drugs) for 6 months along with radiation (SBRT) to each site. I was nervous because I hadn’t done well with just a little Lupron with the first radiation, but I was willing to try it if it could help.

While my PSAs did look good while I was on the hormone therapy and for a while after, my PSA started to rise after my testosterone levels recovered. I had another PSMA scan and an MRI. These showed two new lymph nodes and recurrence in my prostate bed. At that point, I was offered another trial, the LUNAR trial, which was designed with the hope that the new radioactive lutetium drug would kill disease we couldn’t see, and since hormone therapy (even the intense one) didn’t work, I was interested. I was nervous because it was a randomized trial, but after so many recurrences, I wanted to try it. I was randomized to the group that received the two cycles of the lutetium drug followed by SBRT. I had another PSMA scan after the two treatments to prepare for SBRT and this time, my PSA went down and stayed down. I had another PSMA scan 1 year later, and 2 years later, and both times they were clear. I’ve been disease‐free for 2 and a half years now and continue to follow up with my team.

Today, I am very happy. I have been dealing with prostate cancer for over a decade. Ever since the call right after the surgery that it will come back, I have felt this has been a chronic process. I have felt fortunate to have access to so many trials, and, even though two of them didn’t work, I feel like I received cutting‐edge care. And this last one seems to have done the trick.

CONCLUSIONS

Although localized prostate cancer can be cured with radical prostatectomy or definitive radiotherapy in many patients, recurrences unfortunately can be common. These recurrences range in spectrum from a localized recurrence, to a regional nodal recurrence, to true metastatic disease and can sometimes plague patients in succession. In the current case, the patient received guideline‐concordant care after his first recurrence, with early salvage radiotherapy delivered upon a PSA rise to greater than 0.2 but less than 0.5 ng/mL. Advanced imaging was used to guide the design of his radiotherapy fields and revealed both a local recurrence and nodal disease. He was treated on a clinical trial of ultrahypofractionated radiotherapy, with a plan for 6 months of hormonal therapy; radiotherapy fields included the prostate fossa and elective nodes, encompassing all sites of gross disease on the PSMA PET/CT. Despite this approach, he developed a recurrence fairly quickly, highlighting the potential of occult disease even with a positive PSMA PET/CT to direct treatment.

This patient’s subsequent clinical course illustrates the benefits and pitfalls of an approach anchored on SBRT‐based MDT with systemic intensification. His second recurrence, after PSMA‐influenced salvage radiotherapy, reflected an out‐of‐field recurrence in M1a station lymph nodes. His PSA responded on the SATURN trial, but he was among the 50% of patients who had a detectable PSA level within 6 months of testosterone recovery (underscoring the importance of monitoring eugonadal progression‐free survival, and not just progression‐free survival). His third recurrence was successfully treated with the combination approach used on the investigational arm of the LUNAR trial, suggesting the potential benefit of that approach even in patients with multiple recurrences.

Every aspect of this patient’s care—from the refinement of salvage radiotherapy to the optimization of metastasis‐directed SBRT—is currently being studied in large, randomized trials, highlighting the quickly shifting landscape of the management of recurrent prostate cancer. A multidisciplinary, evidence‐based approach is essential to care. Somewhat uniquely, each of these patient’s three recurrences were treated on an institutional, investigator‐initiated trial, with the last one tentatively holding the promise for a cure.

CONFLICT OF INTEREST STATEMENT

Amar Kishan reports grants/contract from Janssen Biotech Inc., Novartis, Point Biopharma, Varian Medical Systems Inc., and ViewRay Technologies Inc.; personal/consulting fees from Boston Scientific Corporation, Janssen Biotech, Lantheus, Novartis, and Varian Medical Systems Inc.; and stock options in MiraDx outside the submitted work. Adam E. Singer reports personal/consulting fees from AVEO Pharmaceuticals Inc., Bristol Myers Squibb Company, Eisai Company Ltd., and Exelixis Inc. outside the submitted work. Kekoa Taparra reports personal/consulting fees from Genentech outside the submitted work. Nicholas G. Nickols reports grants/contracts from Lantheus outside the submitted work. Johannes Czernin reports personal/consulting fees from Aktis Oncology, Coretag, and IsoRay Inc.; support for other professional activities from Trethera; and stock ownership in Sofie outside the submitted work. Jeremie Calais reports personal/consulting fees from Amgen, Astellas Pharma, Bayer, Blue Earth Diagnostics, Coretag, Curium US LLC, DS Pharma, FibroGen, GE Healthcare, IsoRay Inc., Janssen Pharmaceuticals, Lantheus, Lightpoint Medical, Novartis, Nucleus RadioPharma, Nucs AI, Pfizer, Point Biopharma, Radiopharm Theranostics, Sanofi, Siemens, Sofie, and Telix; and support for other professional activities from Curium US LLC, GE Healthcare, IBA RadioPharma Solutions, Lantheus, Monrol, Novartis, Point Biopharma, RadioMedix, Telix outside the submitted work. John K. Lee reports grants/contracts from PromiCell Therapeutics Inc.; personal/consulting fees from Hierax Therapeutics Inc., ImmunityBio Inc., Lyell Immunopharma, and PromiCell Therapeutics Inc.; a patent (applied for) licensed by PromiCell Therapeutics Inc.; stock options in PromiCell Therapeutics, Inc.; and service as a fiduciary officer of PromiCell Therapeutics Inc. outside the submitted work. Matthew B. Rettig reports grants/contracts from Johnson & Johnson Health Care Systems Inc., Lantheus, Merck, the US Department of Defense, and the US Department of Veterans Affairs; personal/consulting fees from AVEO Pharmaceuticals Inc., Immune Bio, Lantheus, and Novartis; and support for other professional activities from Bayer, F. Hoffmann‐La Roche, FibroGen, Johnson & Johnson Health Care Systems Inc., ORIC, and PleXus Communications outside the submitted work. The remaining authors disclosed no conflicts of interest.