Hellenic Urology

REVIEW ARTICLE
Year
: 2020  |  Volume : 32  |  Issue : 3  |  Page : 128--131

Optimizing anticancer therapy in newly diagnosed metastatic castration sensitive prostate cancer


Anastasios Thanos 
 Department of Urology, Ygeias Melathron Hospital, TYPET, Athens, Greece

Correspondence Address:
Anastasios Thanos
Department of Urology, Ygeias Melathron Hospital-TYPET, Therianou 4-6, Athens, PC:11473
Greece

Abstract

Historically, androgen deprivation therapy has been the standard of care in the management of metastatic castration sensitive prostate cancer (mCSPC). However, during the past 5 years, numerous different treatment options have become available and have been set under investigation. The addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and has become a new standard of care. New drugs targeting androgen receptor axis, local therapy including surgery, radiotherapy, and brachytherapy as well as metastatic-directed treatments have also demonstrated promising outcomes. In this work, the available data on all treatment modalities employed in mCSPC are being reviewed.



How to cite this article:
Thanos A. Optimizing anticancer therapy in newly diagnosed metastatic castration sensitive prostate cancer.Hellenic Urology 2020;32:128-131


How to cite this URL:
Thanos A. Optimizing anticancer therapy in newly diagnosed metastatic castration sensitive prostate cancer. Hellenic Urology [serial online] 2020 [cited 2021 Jun 15 ];32:128-131
Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/3/128/310048


Full Text



 Introduction



Metastatic, castration-sensitive prostate cancer (mCSPC) accounts for approximately 3% of all new prostate cancer diagnoses in US. Historically, androgen deprivation therapy (ADT) has been the standard of care. Although the majority of patients have an initial response to ADT, most men with metastases have progression to castration resistant prostate cancer (CRPC) within a median of approximately 1 year. Resistance to ADT is largely driven by the reactivation of androgen receptor signaling through persistent adrenal androgen production, up regulation of intratumoral testosterone production, modification of the biologic characteristics of androgen receptor and steroidogenesis parallel pathways. The treatment of mCSPC has significantly changed over the past 5 years. Since 2015, two clinical trials, CHAARTED and STRAMPETE arm C, demonstrated that upfront docetaxel plus ADT improves overall survival (OS) in patients with mCSPC. Then in 2017, two clinical trials, LATITUDE and STAMPEDE arm G showed that upfront abiraterone plus prednisone plus ADT improves OS to a similar degree as docetaxel plus ADT did. These clinical trials improved the prognosis for patients with mCSPC for the first time; however they also present clinically with a challenge to optimize treatment selection for individual patients among ADT alone, ADT plus docetaxel and ADT plus abiraterone.[1],[2],[3] In this work, we review current literature on the management of mCSPC.

 Evolving Treatment of Metastatic Castration Sensitive Prostate Cancer



Androgen deprivation therapy

Prostate cancer is a classic androgen-sensitive cancer. The effectiveness of ADT at all clinical stages of prostate cancer is clear and significant. In other words, if testosterone is eliminated, it is possible to easily control the disease. Accordingly, approximately 90% of patients with mCSPC will respond to initial treatment with ADT. There are multiple mechanisms of action to block testicular production of androgens, including orchiectomy, luteinizing hormone releasing hormone (LHRH) agonist to prevent luteinizing hormone (LH) production and LHRH antagonists to decrease LH secretion. The first generation of antiandrogens (flutamide, nilutamide and bicalutamide) is not recommended as monotherapy for mCSPC, however, they are frequently used when LHRH agonists are initiated to prevent testosterone flare. Combined androgen blockage with first-generation antiandrogens can be considered, but data supporting the benefits are limited. Recent investigations have studied the optimal dosing schedule of ADT to balance efficacy with patient quality of life (QoL). In a phase III, clinical trial of 3040 men with newly diagnosed prostate cancer, SWOG studied whether intermittent ADT is noninferior to continuous ADT.[4] All patients were initially treated with 7 months of continuous or intermitted ADT then randomly assigned to continuous or intermittent ADT if they had an ongoing PSA response. Unsurprisingly, intermittent ADT was associated with improved QoL 3 months after randomization, but not later because of the variable period of time “off” therapy. However, intermittent ADT was not found to be noninferior to continuous ADT with respect to OS (5.8 years vs. 5.1 years, hazard ratio: 1.10), but rather the results were inconclusive. However, SWOG 9346 raised concerns about intermittent ADT, thus perpetuating continuous ADT as the favor for mCSPC. Analyses of several clinical trials have suggested that more aggressive upfront treatments could translate to improved outcomes for patients with mCSPC. In a subgroup analyses of 1345 patients from SWOG 9346, lower values after 7 months of continuous ADT were predictive of improved median OS. Specifically, the 3838 (25%) of patients with a PSA >4 ng/ml had a median OS of 13 months, whereas 602 (45%) of patients with a PSA <0.2 ng/ml had a median OS of 75 months. A follow-up analysis from the PR-7 trial in men with biochemically recurrent prostate cancer, found that lower testosterone levels were predictive of improved cancer specific survival and time to CRPC.[5] These studies suggested that deeper androgen blockage could improve clinical outcomes from patients with mCSPC.

Androgen deprivation therapy plus docetaxel

To date 3 clinical trials have investigated the efficacy of ADT plus docetaxel: CHAARTED, STAMPEDE arm C, and GETUG-AFU 15.[6],[7],[8],[9] CHAARTED was a phase III clinical trial that randomly assigned 790 men with mCSPC to receive ADT plus docetaxel or ADT alone. Docetaxel without daily prednisone was administered every 3 weeks for a total of 6 cycles. The primary outcome median OS was 13.6 months longer for patients treated with ADT plus docetaxel than for patients receiving ADT alone (57.6 months vs. 44 months, respectively). ADT plus docetaxel also improved median time to progression compared with ADT alone (20.2 months vs. 11.7 months). Docetaxel has a significant toxicity profile that differs from that of ADT, and 29% of patients treated with ADT plus docetaxel reported any Grade 3-4 adverse events. The most frequently reported grade — adverse events were neutropenia (12.1%) and fatigue (4.1%). A subgroup analysis was performed in CHAARTED examining median OS by extend of disease present. Investigators found that only patients with high volume disease, defined as the presence of visceral metastases or at least 4 bone lesions with one or more beyond the vertebral bodies and pelvis, benefit from ADT plus docetaxel (median OS 51 months vs. 34 months), whereas low volume patients had similar outcomes with ADT alone or with docetaxel.[7]

GETUG-AFU 15 conducted before CHAARTED, was a phase III clinical trial that randomly assigned 385 men with mCSPC to receive ADT alone or ADT plus docetaxel.[9] Median OS was not significantly improved in the ADT plus docetaxel when compared to ADT alone. Furthermore, before use of granulocyte colony-stimulating factor, 4 treatment related deaths occurred in ADT plus docetaxel arm. After publication of CHAARTED, a follow-up analysis of GETUG-AFU 15 data reported median OS by volume of disease, which was collected retrospectively. A nonsignificant trend toward improved OS was seen in high volume disease (39.8 vs. 35.1 months).

With controversial findings between CHAARTED and GETUNG-EFU 15 trials, STAMPEDE arm C showed to further explore whether ADT plus docetaxel improve survival in patients with mCSPC.[6] STAMPEDE randomly assigned 2962 men with locally advance or mCSPC to receive ADT alone (arm C), ADT plus zoledronic acid (arm B), ADT plus docetaxel (arm C). Similar to CHAARTED, ADT plus docetaxel significantly improved median OS. As documented in the other trials, more patients in ADT plus docetaxel reported grade 3 or 4 adverse events than those receiving ADT alone (39 vs. 17%), and one treatment related death. Unfortunately, STAMPEDE did not report outcomes by volume disease. These trials established ADT plus docetaxel as a standard of care for fit patients with high volume mCSPC.

Androgen deprivation therapy plus abiraterone acetate plus prednisone

Similar to docetaxel, abiraterone acetate plus prednisone (AAP) was initially approved for the treatment of mCRPC. There are 3 clinical trials eligible for this particular review. Two trials (LATITUDE and STAMPEDE arm G) compared AAP plus ADT with ADT, one of these (STAMPEDE arm G) as part of multi arm, multi stage design.[7],[8] Both have recently published results. Randomized men with metastatic hormone sensitive prostate cancer between 2011 and 2014 in both trials, AAD was administered in a s single dose of 1000 mg/day together with prednisolone (5 mg daily) to prevent secondary mineral corticoid excess until disease progression, withdrawal of consent or unuxeptable toxicity. LATIDUDE was powered to measure two primary points. Median OS and radiographic progression free survival. ADT plus abiraterone significantly improved OS (not reached vs. 34.7 months) and median radiographic progression-free survival (33.0 vs. 14.8 months). Regarding toxicity, grade 3, 4 adverse events were more common in the ADT plus abiraterone arm (63% vs. 48%). The most frequently reported grade 3, 4 adverse events in the abiraterone arm were mineral corticoid related hypertentions (20%), hypokalemia (11%). On the base of the results from the LATITUDE and STAMPEDE arm G clinical trials, ADT plus abiraterone and prednisone is now considered a standard of care for mCSPC regardless of the disease volume status.

Novel combinations being investigated for metastatic castration sensitive prostate cancer

Enzalutamide is a second-generation antiandrogen that binds to the androgen receptor (AR) with higher affinity than bicalutamide and prevents nuclear translocation of the AR. Enzalutamide is approved as any line treatment of MCRPC. Two phase III clinical trials are evaluating ADT plus enzalutamide in patients with mCSPC: EMZA-MET and ARCHES. ENZA-MED will randomly assign 1000 patients with mCSPC to receive ADT with or without docetaxel plus enzalutamide or ADT with or without docetaxel plus a nonsteroidal androgen antagonist. ENZA-MET is anticipated to read out in 2020.

Apalutamide (ARN-505) is another second-generation antiandrogen that is irreversible AR antagonist. Recently, the SPARTAN trial in men with Mo CRPC apalutamide showed improved survival outcomes, however, it is not currently approved for prostate cancer.[10] ADT plus apalutamide is being studied for mCSPC in the phase III TITAN clinical trial. TITAN is randomly assigning 1000 patients with mCSPC to receive ADT with or without docetaxel plus apalutamide versus ADT alone. TITAN will answer the question of whether the addition of apalutamide to standards of care treatment may improve survival outcomes in mCSPC.[11],[12]

Local treatment of metastatic castration sensitive prostate cancer

Prostate radiation or radical prostatectomy (RP) is not currently recommended for the treatment of patients with de novo metastatic prostate cancer. In some advanced malignancies such as metastatic renal cell carcinoma, patients experience a survival benefit from cytoreductive surgery. This has led to increased interest in the role of local therapy for mCSPC. Although reported studies have important limitations, early results for this approach in mCSPC are promising but warrant further investigation.

Initially, two retrospective SEER database studies found that local therapy combined with systemic therapy improved survival in metastatic prostate cancer. In the first SEER analysis, 8185 patients with stage IV prostate cancer were identified between 2004 and 2010.[13],[14] Of these, 245 (3%) had a RP performed, and 129 (1.6%) patients were treated with brachytherapy. Five year OS and CSS were higher in patients receiving RP (67.4%) and brachytherapy (61%) than those receiving no local treatment. Another SEER study showed improved CSS compared with no definitive treatment. Because of their use of the SEER database both studies have substantial limitations. A third retrospective study used the national cancer database to confirm the findings from previous SEER studies. Of 6382 patients with newly diagnosed mCSPC in this database, 538 men (8.4%) were treated with ADT plus radiotherapy and the remaining men were treated with ADT alone. Men treated with ADT plus radiotherapy had significantly improved OS in multivariate analysis.

In summary, RP and radiotherapy have shown to improve survival in patients with mCSPC. However, the design of reported studies and inconsistent findings indicate that randomized clinical trials are needed before definite therapy is routinely used.

Metastatic direct therapy for oligometastatic prostate cancer

To date, it is unclear whether patients with oligometastatic prostate cancer should be treated differently than patients with high volume disease. Multiple retrospective studies initially suggested that metastatic direct therapy may be safe, feasible, and efficacious in patients with oligometastatic prostate cancer.[15] In a single center study of 40 patients with fewer than 2 bone metastases in the spine, stereotactic bone radiation (SBRT) to the metastatic lesions was associated with estimated local control rate of 95% at 6, 12, and 24 months. Another single center study of 21 patients with oligometastatic disease involving the bone (19 patients), lymph nodes (1 patient), and liver (1 patient) found that SBRT had 100% local control at 6 months and that 53% had undetectable PSA. These studies were followed by a multicenter retrospective study of 112 patients that confirmed SBRT is efficacious in oligometastatic prostate cancer.

With multiple retrospective studies suggesting that metastatic direct therapy maybe efficacious for oligometastatic prostate cancer, a phase II clinical trial STOMP, was initiated to validate the role for metastasis-directed therapy. Two additional ongoing phase III studies CORE and PCXIX will provide OS data for metastatic directed therapy.[16],[17],[18],[19]

 Conclusion



ADT plus docetaxel and ADT plus abiraterone are the contemporary standard treatment at mCSPC. ADT plus docetaxel maybe considered for patients with mCSPC who have good performance status, have high volume disease, desire shorter total treatment time or have concerns of prescription drug costs. ADT plus abiraterone maybe suggested for men with cancer of any volume who desire to minimize hospital visits associated with docetaxel infusions. Patient-specific comorbidities maybe guide treatment selections as well, for example abiraterone plus prednisone maybe avoided in those with diabetes, liver disease, osteoporosis, and docetaxel maybe avoided in those with neuropathy or at high risk for myelosupression. Multiple novel androgen axis inhibitors are being investigated in combination with ADT for treatment of mCSPC. On the basis of retrospective and case controlled series data, local therapy for de novo mCSPC has the potential to augment current systemic therapies. Finally, for patients with oligometastatic prostate cancer, metastasis-directed therapy combined with systemic therapy is promising.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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