Apalutamide for the treatment of metastatic castration-sensitive prostate cancer.

Prostate cancer is the fifth leading cause of cancer-related death among men with the majority of deaths linked to metastatic disease. Accumulating clinical data have confirmed the substantial survival benefit of the addition of docetaxel or androgen signaling inhibitors to androgen deprivation therapy for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide, a next-generation androgen receptor inhibitor, has recently been shown to provide an added survival benefit in the treatment of mCSPC and consequently approved for this indication. This review summarizes the body of evidence with regards to the preclinical activity and clinical efficacy of apalutamide with a specific focus on its efficacy in the treatment of mCSPC.

Strategic Advances in Combination Therapy for Metastatic Castration-Sensitive Prostate Cancer: Current Insights and Future Perspectives.

The contemporary treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved significantly, building on successes in managing metastatic castration-resistant prostate cancer (mCRPC). Although androgen deprivation therapy (ADT) alone has long been the cornerstone of mCSPC treatment, combination therapies have emerged as the new standard of care based on recent advances, offering improved survival outcomes. Landmark phase 3 trials demonstrated that adding chemotherapy (docetaxel) and androgen receptor pathway inhibitors to ADT significantly enhances overall survival, particularly for patients with high-volume, high-risk, or de novo metastatic disease. Despite these advancements, a concerning gap between evidence-based guidelines and real-world practice remains, with many patients not receiving recommended combination therapies. The challenge in optimizing therapy sequences, considering both disease control and treatment burdens, and identifying clinical and biological subgroups that could benefit from personalized treatment strategies persists. The advent of triplet therapy has shown promise in extending survival, but the uro-oncology community must narrow the gap between evidence and practice to deliver the most effective care. Current research is focused on refining treatment approaches and utilizing biomarkers to guide therapy selection, aiming to offer more personalized and adaptive strategies for mCSPC management. Thus, aligning clinical practices with the evolving evidence is urgently needed to improve outcomes for patients facing this incurable disease.

Treatment Landscape for Metastatic Castrate-Sensitive Prostate Cancer: A Review.

With the advent of new therapeutic modalities, management of metastatic castrate-sensitive prostate cancer (mCSPC) has been in flux. From androgen-deprivation therapy to docetaxel to androgen receptor-signaling inhibitors, each agent has heralded a new treatment paradigm. As such, the optimal first-line therapy for mCSPC remains incompletely defined. This review provides a narrative of recent advances to systemic therapy within the mCSPC treatment space, particularly with regard to expansion to triplet therapy.

Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC)-A Potential New Standard of Care.

The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.

Sequencing of Systemic Therapies in the Management of Advanced Prostate Cancer in India: a Delphi-Based Consensus.

INTRODUCTION: With the availability of an increasing number of therapeutic options for advanced prostate cancer (APC), optimal sequencing and combination of therapies have emerged to be the areas of challenges. In the Indian context, there is a dearth of consensus recommendations to guide clinicians regarding optimal sequencing of therapy in APC management. A Delphi-based consensus regarding optimal therapy sequencing in APC management was developed by an expert panel of medical oncologists from across India. METHODS: An expert scientific committee of 11 medical oncologists and an expert panel of 53 medical oncologists from India constituted the panel for the Delphi consensus. In the first phase, a questionnaire with 41 clinical statements was developed in several critical controversial areas in APC treatment. In the second phase, 29 clinical statements were reworked and sent to eight experts to obtain their opinions on best practices. The consensus ratings were based on a 9-point Likert scale. Based on the overall response, statements with a mean score of ≥ 7 with 1 outlier were considered as "consensus." RESULTS: Degarelix was the preferred androgen deprivation therapy (ADT). While ADT plus docetaxel was the preferred option for metastatic castrate-sensitive/naïve prostate cancer patients with high-volume disease, ADT with abiraterone was the preferred choice for low-volume disease. Docetaxel was the preferred first-line treatment option in men who received ADT alone in the castrate-sensitive/naïve setting. For patients progressing on or after docetaxel for metastatic castrate-resistant prostate cancer (without prior abiraterone or enzalutamide), the experts reached a consensus on the use of enzalutamide as the preferred second-line treatment option. No consensus was reached for the third-line treatment options. CONCLUSION: This article is intended to serve as a guide to help clinicians discuss with their patients as part of the shared and multidisciplinary decision-making for improved APC management in India.

Current management of metastatic castration-sensitive prostate cancer.

Prostate cancer affects one in nine men and once metastatic is incurable. The treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved rapidly over the last decade with the addition of upfront intensification with novel hormonal therapies (abiraterone, enzalutamide, apalutamide) or docetaxel in addition to androgen deprivation therapy. In this review, we discuss the phase III studies that lead to the approval of these upfront intensification therapies. We also review the recent approval of relugolix, the first oral, gonadotropin-releasing hormone antagonist for patients with advanced prostate cancer. A comparison of various agents is made and variables that can help in treatment selection are reviewed. We also summarize our current understanding of the role of germline and somatic alterations in the mCSPC setting. Finally, we review the ongoing clinical trials which can change the current treatment paradigm.

Docetaxel dose-intensity effect on overall survival in patients with metastatic castrate-sensitive prostate cancer.

BACKGROUND: Several studies assessed the association of docetaxel dose intensity (DI) and efficacy in metastatic castrate-resistant prostate cancer (mCRPC) patients with contradicting conclusions. In this retrospective analysis, we will assess whether the docetaxel DI used in patients with metastatic castrate-sensitive prostate cancer (mCSPC) is associated with overall survival (OS). METHODS: All patients with mCSPC treated at The Ottawa Hospital Cancer Centre that received docetaxel chemotherapy between June 2014 and September 2017 were identified. The association between relative dose intensity (RDI) and OS was assessed using univariate and multivariable Cox model adjusting for age, Gleason score, burden of disease, visceral involvement, de novo metastases and baseline prostate-specific antigen (PSA). RESULTS: Eighty-one patients were included in the analysis. Only 35 patients (43%) were able to complete the planned treatment with a RDI of at least 90%. On a univariate analysis, higher RDI and number of cycles of docetaxel received were associated with longer OS. For every 10% decrease in RDI, the risk of death increased by 23% (HR 1.23, 95% CI 1.09-1.4, P = 0.001). For every increment of one cycle (and up to six), the risk of death decreased by 27% (HR 0.73, 95% CI 0.61-0.88, P = 0.001). On multivariate analysis, reduced RDI was the only predictor significantly associated with OS (HR 1.18, 95% CI 1.02-1.36, P = 0.026). CONCLUSIONS: Our study suggests that in mCSPC, reduced docetaxel RDI is associated with shorter survival. Unnecessary dose reductions, treatment delays and early discontinuation should be avoided. Granulocyte colony-stimulating factor may be considered to maintain standard DI.

Docetaxel Rechallenge in Patients with Metastatic Prostate Cancer: A Comprehensive Review.

BACKGROUND: Recent years have witnessed a huge shift in the management and prognosis of metastatic prostate cancer with the advent of new-generation anti-hormonal treatments. Docetaxel, which was initially approved in the castrate-resistant prostate cancer setting, has been approved in the earlier course of the disease as it is still castrate sensitive. SUMMARY: Apart from cabazitaxel and in the absence of other effective chemotherapies, docetaxel rechallenge (DR) in patients with proved sensitivity to docetaxel in the earlier stage of the disease remains a possible option. Unfortunately, the pivotal trials rarely reported on the outcomes of docetaxel retreatment which seems a plausible option in patients initially responding to docetaxel and maintaining a minimum progression-free interval of 3-6 months. In this review, a summary of the clinical evidence and potential concerns for the use of DR in patients with metastatic prostate cancer will be presented. Key Messages: Pivotal trials of docetaxel in metastatic castrate-sensitive prostate cancer as well as metastatic castrate-resistant prostate cancer have not reported on the outcomes of DR except in the GETUG-AFU 15 trial where the outcomes were disappointing. Based on the published retrospective data, DR may be effective in patients who initially responded to docetaxel and maintained a progression-free interval exceeding 6 months.

The timing of docetaxel initiation in metastatic castrate-sensitive prostate cancer and the rate of chemotherapy-induced toxicity.

Docetaxel pharmacokinetics are affected by androgen deprivation therapy (ADT), which is attributed to changes in liver metabolism induced by castration. In this retrospective analysis, we assessed whether initiating docetaxel treatment in close proximity to the start of ADT therapy for metastatic castrate-sensitive prostate cancer (mCSPC) is associated with more treatment-related toxicity. We identified all patients with mCSPC treated at The Ottawa Hospital that received docetaxel chemotherapy between June 2014 and September 2017. For each patient, we calculated the time to chemotherapy (TTC) interval between the start of ADT and the first cycle of docetaxel. We checked for an association between TTC and febrile neutropenia (FN), toxicity-induced dose reduction, toxicity-induced treatment delay, and toxicity-induced treatment discontinuation. Eighty-three patients were identified. The median TTC was 67 days (range 3-189). Twenty-three patients (27.7%) experienced FN. Docetaxel toxicity resulted in 8 patients (9.6%) having their treatment delayed, 30 patients (36.1%) having their dose reduced and 18 (21.6%) having their treatment discontinued before completing the scheduled 6 cycles. No correlation was found between the TTC and FN (P = 0.99), docetaxel dose reduction (P = 0.95), treatment delay (P = 0.06), and treatment discontinuation (P = 0.88). The timing of docetaxel treatment initiation in relation to ADT initiation in patients with mCSPC did not affect the rate of treatment-related toxicity. Therefore, there is no indication for upfront chemotherapy delay from start of ADT unless clinical factors warrant a delay in starting chemotherapy. A higher than expected FN rate was identified, and primary prophylaxis should be considered.

Prediction of Time to Hormonal Treatment Failure in Metastatic Castration-Sensitive Prostate Cancer with 18F-FDG PET/CT.

The aim of this prospective investigation was to assess the association of 18F-FDG PET/CT with time to hormonal treatment failure (THTF) in men with metastatic castration-sensitive prostate cancer. Methods: 76 men with metastatic castration-sensitive prostate cancer recruited from 2005 to 2011 underwent 18F-FDG PET/CT and were followed prospectively for THTF, defined as treatment change to chemotherapy or death. Patients who had not switched to chemotherapy were censored at the last follow-up date (median of 36 mo; range, 12-108 mo). Cox regression analyses were performed to examine the association between PET/CT measurements: sum of SUVmax, maximum SUVmax, and average SUVmax for up to 10 of the most active lesions and THTF. Survival probabilities were based on the Kaplan-Meier method. Results: 43 patients had hormonal treatment failure, and 8 died without documented treatment failure. Median THTF was 26.5 mo (95% confidence interval [CI], 15.5-46.6 mo). The THTF-free probability at 5 y was 35% ± 6%. On univariate analysis, all PET parameters, including number of lesions, were statistically significant for THTF. In a reduced multivariate model accounting for clinical variables, only sum of SUVmax (hazard ratio, 1.01; 95% CI, 1.002-1.03; P = 0.024) and number of lesions (hazard ratio, 1.18; 95% CI, 1.08-1.29; P < 0.001) were independently associated with THTF. When sum of SUVmax was grouped into quartile ranges, there was a significantly worse survival probability for patients in the fourth-quartile range than in the first, with a univariate hazard ratio of 6.2 (95% CI, 2.8-13.6; P < 0.001). Conclusion: Sum of SUVmax and number of lesions derived from 18F-FDG PET/CT provide independent prognostic information on THTF in men with metastatic castration-sensitive prostate cancer.

Systemic treatment for metastatic prostate cancer.

The management of metastatic prostate cancer (mPCa) has changed over the past ten years. Several new drugs have been approved with significant overall survival benefits in metastatic castration resistant prostate cancer (PCa) including chemotherapy (docetaxel, cabazitaxel), new hormonal therapies (abiraterone, enzalutamide), Radium-223 and immunotherapy. The addition of docetaxel to androgen deprivation therapy (ADT) versus ADT alone in the castration sensitive metastatic setting has gained significant overall survival benefit particularly for high volume disease. More recently two phase III trials have assessed the efficacy of abiraterone plus prednisone plus ADT over ADT alone in newly high risk castrate sensitive mPCa. Determination of the appropriate treatment sequence using these therapies is important for maximizing the clinical benefit in castration sensitive and castration resistant PCa patients. Emerging fields are the identification of new subtypes with molecular characterization and new therapeutic targets.

Chemotherapy at First Diagnosis of Advanced Prostate Cancer - Revolution or Evolution? Findings from a British Uro-oncology Group UK Survey to Evaluate Oncologists' Views on First-line Docetaxel in Combination with Androgen Deprivation Therapy in Castrate-sensitive Metastatic and High-risk/Locally Advanced Prostate Cancer.

AIMS: There have been three randomised trials investigating docetaxel in combination with androgen deprivation therapy as first-line therapy for hormone-sensitive metastatic and locally advanced/high-risk prostate cancer. The largest of these studies, UK STAMPEDE trial, recently presented in June 2015. The aim of this survey was to evaluate if oncologists' practice has changed as a result of these studies, or if their practice is likely to change in different clinical settings in the future. MATERIALS AND METHODS: The British Uro-oncology Group issued a semi-structured online questionnaire to its membership of 160 specialist urological oncologists practising in the UK. Links to the abstracts of GETUG-AFU-15, E3805 CHAARTED and STAMPEDE were attached with the survey for respondents to review before completing the survey. RESULTS: In total, 111 participants completed the survey; 87% stated that STAMPEDE will influence their clinical practice in the future. Almost all (96%) would offer docetaxel with androgen deprivation therapy to men presenting with high volume metastatic prostate cancer. Fewer oncologists would offer this treatment to men with low volume metastatic prostate cancer, locally advanced or relapsed disease. Various patient- and disease-related factors were considered in decision making, as well as resource implications. CONCLUSIONS: This survey reports oncologists' attitudes towards a major change in practice in the standard of care for men with newly diagnosed advanced prostate cancer in the UK. The survey highlighted the complexities surrounding the clinical implementation of the data from these studies, including changes in referral pathways, with the early involvement of oncologists in such patients' care, increases in workloads for oncologists and chemotherapy units and the need for national approval for re-imbursement of these treatments.