Progression-directed therapy in patients with oligoprogressive castration-resistant prostate cancer

Abstract

Purpose

Oligoprogressive lesions are observed in a subset of patients who progress to castration-resistant prostate cancer (CRPC), while other lesions remain controlled by systemic therapy. This study evaluates the impact of progression-directed therapy (PDT) on these oligoprogressive lesions.

Materials and Methods

This retrospective study included 40 patients diagnosed with oligoprogressive CRPC. PDT was performed for treating all progressive sites using radiotherapy. Fifteen patients received PDT using radiotherapy for all progressive sites (PDT group) while 25 had additional first-line systemic treatments (non-PDT group). In PDT group, 7 patients underwent PDT and unchanged systemic therapy (PDT-A group) and 8 patients underwent PDT with additional new line of systemic therapy on CRPC (PDT-B group). The Kaplan–Meier method was used to assess treatment outcomes.

Results

The prostate specific antigen (PSA) nadir was significantly lower in PDT group compare to non-PDT group (p=0.007). A 50% PSA decline and complete PSA decline were observed in 13 patients (86.7%) and 10 patients (66.7%) of PDT group and in 18 patients (72.0%) and 11 patients (44.0%) of non-PDT group, respectively. The PSA-progression free survival of PDT-B group was significantly longer than non-PDT group. The median time to failure of first-line systemic therapy on CRPC was 30.2 months in patients in PDT group and 14.9 months in non-PDT group (p=0.014). PDT-B group showed a significantly longer time to progression than non-PDT group (p=0.025). Minimal PDT-related adverse events were observed.

Conclusions

PDT can delay progression of disease and enhance treatment efficacy with acceptable tolerability in oligoprogressive CRPC.

Graphical Abstract

INTRODUCTION

Castration-resistant prostate cancer (CRPC) develops when hormone-sensitive prostate cancer (HSPC) exhibits progression despite castration, potentially due to castration-resistant clones. The median survival of metastatic CRPC (mCRPC) is approximately 35 months, although this may vary with prognostic factors and the use of second- and third-line systemic treatment regimens [1]. The standard treatment for CRPC includes inhibition of androgen biosynthesis (abiraterone) and androgen receptors (enzalutamide) or chemotherapy in combination with androgen deprivation therapy (ADT). However, these measures are typically associated with substantial financial costs and increased risk of adverse effects [2].

The progression of prostate cancer (PC) can range from loco-regional to widespread metastatic disease, with oligoprogression being observed in a subset of patients exhibiting advancement of certain lesions to castration-resistance while all others remain responsive to ongoing systemic treatment [3,4]. The increasing popularity of local treatment of primary or metastatic lesions in HSPC has been accompanied by the introduction of novel treatment approaches such as complementing systemic treatment regimens for oligoprogressive CRPC with progression-directed therapy (PDT) [3,4,5,6,7]. The standard systemic treatment regimen typically includes administration of abiraterone, enzalutamide, or docetaxel upon exacerbation of the disease to CRPC; however, PDT is emerging as an alternative treatment strategy for oligoprogressive disease sites as it can substantially delay the need of additional systemic treatment for CRPC while also enhancing their efficacy [3,4,8,9,10,11,12,13,14]. Although there is a lack of evidence from randomized controlled studies in this field, previous studies suggest that PDT may delay the need for subsequent systemic therapy and also improve survival outcomes in patients with oligoprogressive CRPC [8,9,11,15,16,17].

This study aims to evaluate the characteristics of oligoprogression in a cohort of patients treated at a single center and examine the effects of PDT on treatment outcomes.

MATERIALS AND METHODS

This retrospective study, approved by the Ethics Committee of the Kyungpook National University Chilgok Hospital (approval number: KNUCH 2023-08-024), and the written informed consent was waived due to the retrospective nature of the study. This study included 40 patients diagnosed with oligoprogressive CRPC at a single institution between 2018 and 2022. CRPC was diagnosed upon observation of castration levels of serum testosterone <50 ng/dL and evidence of biochemical or radiological progression (in accordance with the European Association of Urology guidelines) [18]. Oligoprogression was defined as ≤3 progressive lesions at known metastatic sites and/or appearance of new metastasis and/or local recurrence. The patents with a progressive lesion in the prostate were allowed up to two progressive metastatic lesions. All patients underwent radiographical examination using conventional imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), and bone scan.

After appropriate consultations between the patients and their respective physicians, PDT was carried out with the intention of treating all progressive sites detected via conventional imaging using radiotherapy at the earliest time after progression was confirmed. Prostate and gross lymph node metastases were treated with 70–74 Gy (2–2.5 Gy per fraction). For patients with high-risk or N1 stage at the time of initial diagnosis, prophylactic pelvic nodal radiation was performed with 44–50.4 Gy (1.8–2 Gy per fraction). For single or oligoprogression in bone (especially, spine), lung, or visceral organ, stereotactic body radiation therapy (SBRT) was performed. Regarding dose and fractionation of SBRT, there were variable from single dose of 16 Gy to multiple doses of 40–54 Gy in 3–4 fractions. For bone metastasis that were not treated with SBRT, radiation dose of 39–50.4 Gy (1.8–3 Gy per fractions) were administered. All patients underwent recording of medical history, physical examination, prostate specific antigen (PSA), and imaging every 1–3 months.

A comparative analysis of CRPC patients who underwent PDT with/without additional first-line systemic treatment for CRPC (PDT group; n=15) and those who underwent first-line systemic treatment only (non-PDT group; n=25) was carried out. The former group included seven patients who underwent PDT with continuation of existing systemic therapy (PDT-A group) and eight patients who underwent PDT along with addition of a new line of anti-cancer treatments for CRPC (PDT-B group), as follows:

• • PDT group

  • - PDT-A group: PDT+previous systemic therapy (ADT)
  • - PDT-B group: PDT+previous (ADT) & additional systemic therapy*

• • Non-PDT group: previous (ADT) & additional systemic therapy*

• *Additional systemic therapy: androgen receptor axis-targeted agents (ARTAs) or docetaxel chemotherapy for CRPC.

The Wilcoxon and Fisher’s exact tests were used to compare continuous and nominal variables between groups, respectively, while the Kaplan–Meier method was used to assess failure-free survival of first-line systemic therapy for CRPC, radiographic progression-free survival, and PSA-progression free survival. PSA-progression free survival was defined as the time between diagnosis of oligoprogressive CRPC and PSA progression (2 ng/mL increase from PSA nadir), and patients without PSA decease were considered to have PSA progression at time point 0. Cox regression analyses were used to identify clinical factors associated with failure-free survival of first-line systemic therapy for CRPC, while adverse effects of PDT were evaluated using the CTCAE (Common Terminology Criteria for Adverse Events), v5.0 (National Cancer Institute). All statistical analyses were performed using SPSS version 16.0 for Windows (SPSS Inc.), and a p-value of <0.05 was considered statistically significant.

RESULTS

The mean follow-up duration was 24 months (range, 6–61 months) and 23 months (range, 10–47 months) in the PDT and non-PDT groups, respectively. Table 1 shows patient characteristics by treatment group. The mean age and PSA at the time of CRPC diagnosis were 72.6±8.2 years and 8.9±10.3 ng/mL, respectively. The ISUP (International Society of Urological Pathology) grade group (GG) on initial diagnosis of PC was 2.5% in GG2, 10.0% in GG3, 40.0% in GG4, and 47.5% in GG5. Furthermore, 33.3% of the PDT group and 42.0% of the non-PDT group had a history of definitive treatment including radical prostatectomy or radiotherapy. The treatment groups did not differ significantly in terms of age, PSA levels, PSA doubling time, number of progressive sites, location of progressive sites, and presence of disease progression within the prostate at the time of CRPC diagnosis.

Table 1. Patient and tumor characteristics.

		Total (n=40)	PDT group (n=15)	Non-PDT group (n=25)	p-value
Age at diagnosis (y)		68.78±7.57	69.07±8.33	68.60±7.25	0.853
PSA at diagnosis (ng/mL)		107.66±175.61	118.02±182.09	101.44±175.11	0.777
Stage at diagnosis
	T (3a/3b/4)	6/27/7	3/11/1	3/16/6	0.434
	N (0/1)	23/17	9/6	14/11	0.804
	M (0/1)	22/18	8/7	14/11	0.870
	Burden of metastasisa (low/high/M0)	13/5/22	6/1/8	7/4/14	0.657
ISUP grade group at diagnosis					0.514
	1	0 (0.0)	0 (0.0)	0 (0.0)
	2	1 (2.5)	1 (6.7)	0 (0.0)
	3	4 (10.0)	1 (6.7)	3 (12.0)
	4	16 (40.0)	7 (46.7)	9 (36.0)
	5	19 (47.5)	6 (40.0)	13 (52.0)
Initial treatment at diagnosis					0.428
	Radical prostatectomy	12 (30.0)	4 (26.7)	8 (32.0)
	Radiotherapy	4 (10.0)	1 (6.7)	3 (12.0)
	ADT	22 (55.0)	8 (53.3)	14 (56.0)
	ADT+ARTA	0 (0.0)	0 (0.0)	0 (0.0)
	ADT+docetaxel	2 (5.0)	2 (13.3)	0 (0.0)
Duration of ADT before CRPC diagnosis (mo)		37.2±31.0	38.2±34.1	36.6±29.7	0.878
Age at CRPC diagnosis (y)		72.6±8.2	73.3±9.0	72.2±7.8	0.678
PSA at CRPC diagnosis (ng/mL)		8.9±10.3	6.0±6.9	10.6±11.7	0.176
PSA doubling time from CRPC diagnosis (mo)		3.8±2.5	4.1±2.8	3.6±2.4	0.548
Number of oligoprogression lesions					0.880
	1	29 (72.5)	12 (80.0)	17 (68.0)
	2	7 (17.5)	2 (13.3)	5 (20.0)
	3	4 (10.0)	1 (6.7)	3 (12.0)
Oligoprogression site
	Prostate (including prostatectomy bed)	14	6	8
	Prostate (including prostatectomy bed)+bone	4	2	2
	Prostate (including prostatectomy bed)+adrenal gland	1	0	1
	Lymph node	5	1	4
	Lymph node+bone	3	0	3
	Bone	12	5	7
	Lung	1	1	0
Oligoprogression site					0.804
	Pelvis only	17 (42.5)	6 (40.0)	11 (44.0)
	Extra-pelvis	23 (57.5)	9 (60.0)	14 (56.0)
Prostate progression (including prostatectomy bed)		18 (45.0)	8 (53.3)	10 (40.0)	0.412
Visceral organ progression		2 (5.0)	1 (6.7)	1 (4.0)	>0.999

Values are presented as mean±standard deviation, number only, or number (%).

PDT, progression-directed therapy; PSA, prostate specific antigen; ISUP, International Society of Urological Pathology; ADT, androgen deprivation therapy; ARTA, androgen receptor axis-targeted agents; CRPC, castration-resistant prostate cancer.

^a:Burden of metastasis is based on Chaarted trial criteria.

Approximately 80.0% of the PDT group and 68.0% of the non-PDT group exhibited single progressive lesions, and the sites most frequently targeted by PDT were the prostate or prostate bed (n=14) and bone (n=12). Table 1 shows the locations of PDT. Of the eight patients in the PDT-B group, seven received ARTAs such as abiraterone or enzalutamide, and one received docetaxel chemotherapy in addition to PDT. In the non-PDT group, seven patients received ARTAs and three patients received docetaxel chemotherapy without PDT.

The mean nadir PSA levels were 0.73±1.43 ng/mL in the PDT group and 6.91±10.40 ng/mL in the non-PDT group (p=0.007). A decrease in PSA levels of at least 50% in response to treatment (50% PSA decline) was observed in 13 patients (86.7%) in the PDT group and 18 patients (72.0%) in the non-PDT group, while 10 patients (66.7%) in the PDT group and 11 patients (44.0%) in the non-PDT group exhibited complete PSA decline (PSA <0.2 ng/mL) (Table 2). PSA-progression free survival was significantly higher in the PDT-B group compared to the non-PDT group (p=0.049; Fig. 1C). Four patients (57.1%) in the PDT-A group exhibited progression after PDT and were treated using additional first-line systemic treatment measures for CRPC. The mean time to failure of first-line systemic therapy for CRPC was 30.2 months in the PDT group and 14.9 months in the non-PDT group (p=0.014; Fig. 1A). Moreover, the time to progression was significantly longer in the PDT-B group compared to the non-PDT group (p=0.025; Fig. 1B). The Cox hazards model examining predictive factors showed an association between PDT and progression free survival (hazard ratio 5.501, 95% confidence interval 1.214–24.923, p=0.027). Grade 1 PDT-related adverse effects were observed in two patients diagnosed with hematochezia (n=1) and dysuria (n=1). Grade 2 PDT-related adverse effect in one patient with skin allergic reaction. None of the patients exhibited major adverse events.

Table 2. Treatment characteristics and outcomes.

		Total (n=40)	PDT group (n=15)	Non-PDT group (n=25)	p-value
Initial treatment at CRPC diagnosis
	Local therapy only	7	7	0
	Local therapy+ARTA	7	7	0
	Local therapy+docetaxel	1	1	0
	ARTA	18	0	18
	Docetaxel	7	0	7
Toxicity of local therapya
	Grade 0		12 (80.0)
	Grade 1		2 (13.3)
	Grade 2		1 (6.7)
	Grade 3 or 4		0 (0.0)
Mean follow-up duration (mo)		23.15±11.52	23.73±14.67	22.80±9.47	0.808
50% PSA decline rate		31 (77.5)	13 (86.7)	18 (72.0)	0.440
Complete PSAb decline rate		21 (52.5)	10 (66.7)	11 (44.0)	0.165
PSA nadir (ng/mL)		4.59±8.75	0.73±1.43	6.91±10.40	0.007
Time to PSA nadir (mo)		4.55±2.90	5.87±2.90	3.76±2.65	0.024
PSA progressionc rate		18 (45.0)	4 (26.7)	14 (56.0)	0.071
Mean PSA progressionc free survival (mo)		19.32±11.10	19.07±13.76	13.08±8.71	0.099
Failure rate of 1st systemic therapy on CRPC		15 (37.5)	3 (20.0)	12 (48.0)	0.077
Mean time to failure of 1st systemic therapy from CRPC diagnosis (day)		448.95±314.16	575.20±416.34	373.20±208.16	0.048

Values are presented as number only, number (%), or mean±standard deviation.

PDT, progression-directed therapy; CRPC, castration-resistant prostate cancer; ARTA, androgen receptor axis-targeted agents; PSA, prostate specific antigen.

^a:Toxicity of local therapy was based on CTCAE (Common Terminology Criteria for Adverse Events) v5.0.

^b:Complete PSA decline was defined as a decrease of less than 0.2 ng/mL.

^c:PSA progression was defined as an increase of 2 ng/mL or more from PSA nadir.

Fig. 1. (A) Kaplan–Meier (K-M) survival plot comparing time to failure of first-line systemic therapy between progression-directed therapy (PDT) and non-PDT groups (p=0.014). (B) Kaplan–Meier survival plot comparing progression-free survival between PDT-B and non-PDT groups (p=0.025). (C) Kaplan–Meier survival plot comparing PSA-progression free survival between PDT-B and non-PDT groups (p=0.049). CRPC, castration-resistant prostate cancer; PSA, prostate specific antigen.

DISCUSSION

Historically, systemic treatment strategies for CRPC have been the most widely accepted. However, the ability of local treatment measures such as radiotherapy and surgery for metastatic or recurrent sites to suppress disease progression rather than locally control invasive symptoms of disease remains unclear. Recent studies have demonstrated the efficacy of a novel treatment approach involving addition of PDT to systemic therapy in patients exhibiting oligoprogressive CRPC. Therefore, the current retrospective single center study evaluated the effects of PDT on treatment outcomes in 40 patients diagnosed with oligoprogressive CRPC using conventional imaging. PDT was performed with the intention of treating all progressive sites using metastasis-directed therapy, stereotactic body radiation, or fractionated radiotherapy for metastasis or local recurrence. Despite the small sample size and short follow-up period, the findings of this study demonstrated that PDT delayed progression of oligoprogressive CRPC, enhanced the efficacy of subsequent systemic therapy, and exhibited acceptable tolerability with minimal PDT-related adverse events (based on the CTCAE scoring system).

Oligoprogressive disease, defined as the progression of a limited number (typically a maximum of 3) of lesions while the majority remain responsive to ongoing systemic therapy, typically occurs in a subgroup of CRPC patients and is caused by the evolution of one or more subclones to become resistant to ongoing systemic therapy [19]. These variations in responses to treatment reflect the heterogeneity of subclones within the different cancer spots [20]. PDT may be effective in reducing treatment-resistant clones, thereby improving the efficacy of subsequent systemic therapy [12,16]. Therefore, a therapeutic rationale for treatment of these sites is compelling, given the proposed etiology, and clarification of disease status is essential when considering treatment strategies. Although there is a general lack of consensus on the definition of oligoprogressive disease, the current study defined it as “≤3 progressive lesions at known metastatic sites and/or the appearance of new metastasis and/or local recurrence observed using conventional imaging modalities”. The imaging modality used can also play a significant role in the number of progressive lesions identified and the selection of suitable patients for PDT. Lohaus et al. [15], examined the efficacy of ⁶⁸prostate specific membrane antigen positron emission tomography-guided local ablative radiotherapy in 15 oligometastatic CRPC patients and found that 11 patients exhibited a decline in PSA values while six showed no PSA progression for >12 months. These promising findings emphasize the importance of accurate detection of progressive lesions using advanced imaging as a prerequisite for PDT treatment success in patients with oligoprogressive CRPC. In the current study, a diagnosis of oligoprogression was made upon observation of ≤3 lesions using conventional imaging such as CT, MRI, and bone scans. This suggests that PDT can potentially improve the efficacy of subsequent treatment even in the absence of novel imaging techniques.

Several studies to date have examined the role of PDT in patients with oligoprogressive CRPC [8,10,11,12,13,14]. Deek et al. [11], examined 68 patients diagnosed with oligoprogressive CRPC (≤5 lesion) and treated using metastasis-directed stereotactive ablative radiotherapy and found that 78% exhibited a PSA decline while 29% exhibited undetectable PSA nadirs. Additionally, patients undergoing metastasis-directed therapy for oligoprogressive lesions exhibited improvements in median time to PSA failure, time to next intervention, and distant metastasis-free survival when compared to patients receiving systemic therapy alone. This suggests that complementing systemic treatment strategies for oligoprogressive mCRPC with metastasis-directed therapy is beneficial. Yoshida et al. [8], evaluated the effect of PDT on response to subsequent treatment using androgen receptor axis-targeted drugs and found that 86.7% and 66.7% patients treated with PDT exhibited PSA declines and 50% PSA declines, respectively. Moreover, the PSA-progression free survival was significantly longer in the PDT group compared to the non-PDT group. The authors concluded that PDT was associated with improved responses to subsequent treatment using ARTAs, longer survival, and better oncological outcomes [8]. Another multicenter retrospective analysis showed that, in a subset of patients diagnosed with oligoprogressive CRPC while on ADT, initiation of second-line systemic therapies could be meaningfully postponed when the oligoprogressive lesions were treated with local radiotherapy [12].

This study had several limitations including a small sample size, recruitment of patients from a single institution only, and considerable heterogeneity in patient characteristics, imaging and treatment modalities used. Several limitations also constrain the analysis of prognostic or predictive factors in this study. There is insufficient evidence demonstrating the presence of oligoprogressive PC. Although some studies have shown emergence of subclones following therapy, the overall mechanisms underlying oligoprogression remain poorly understood. Further confounding is introduced by the inherent limitations of imaging which prevent visualization of all drug-resistant sites of disease or clones. These limitations highlight the need for standardization of study designs and outcome reporting methods. Further research using prospective trial designs that compare new and conventional imaging modalities are also necessary.

CONCLUSIONS

This retrospective study showed that PDT can delay progression of oligoprogressive CRPC and enhance the efficacy of subsequent systemic therapy with acceptable tolerability. Further research using well-designed prospective trials is necessary to confirm the efficacy of PDT in patients with oligoprogressive CRPC.