Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer
A living guideline by ASCO.
These guideline summaries are shared for educational purposes only and are not intended to direct patient care. For detail on the specific recommendations and information about the evidence considered by the guideline developer, we encourage you to go to the original guideline statement cited below.
Good Practice Statements
Metastatic castration-resistant prostate cancer (mCRPC; androgen pathway modulation resistant [APMR]) is defined as castrate levels of testosterone (<50 ng/mL or 1.7 nmol/L) with evidence of either new or progressive metastatic disease on radiologic assessment or two consecutive rising PSA levels (minimal start value is 1.0 ng/mL) in the setting of existing metastatic disease.
The Panel recommends both germline and somatic testing for patients with metastatic prostate cancer at the earliest available opportunity. Additional recommendations and discussion regarding the same are available in the Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline.
The Panel recommends personalizing treatment based on prior therapies received during castration-sensitive setting, while also accounting for each patient’s clinical status, cancer-related symptoms and signs, therapy-related toxicities, potential drug interactions, cost, and drug availability.
The Panel recommends continuation of androgen-deprivation therapy (ADT), or surgical castration, to maintain castrate levels of testosterone for every patient with mCRPC (APMR).
The Panel recommends early integration of palliative and supportive care teams for symptom management and to review goals of care for patients with mCRPC (APMR). Additional information on the same is available in the Palliative Care for Patients With Cancer: ASCO Guideline Update.
The Panel recommends the use of bone-protective agents like denosumab (RANK ligand inhibitor) or zoledronic acid (bisphosphonate) for patients with bone metastases to lower the risk of skeletal-related events (SREs). Additional recommendations on the same are available in the Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline.
Limited randomized clinical trial data exist for optimal sequencing of therapies for patients with mCRPC (APMR), as certain therapies studied in the mCRPC (APMR) setting are now being utilized earlier during castration-sensitive disease.
Treatment
The Panel recommends homologous recombination repair (HRR) testing prior to initiation of systemic therapy (see the Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline). If positive for BRCA1/2 alterations, then preferred options include either of niraparib + abiraterone, olaparib + abiraterone, or talazoparib + enzalutamide.
The Panel suggests the combination of talazoparib and enzalutamide for patients with any of the other HRR alterations (PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12).
The Panel recommends either enzalutamide or chemotherapy utilizing docetaxel for patients with visceral disease (lung and/or liver metastases) and regardless of HRR alterations (please refer to above recommendations for preferred recommendations in patients with HRR alterations).
The panel recommends abiraterone with prednisone, darolutamide, apalutamide, or cabazitaxel in selected patients with visceral disease.
The Panel recommends docetaxel, abiraterone plus prednisone, enzalutamide with radium 223, or sipuleucel-T for patients with mCRPC (APMR) without visceral metastases. The Panel recommends radium 223 monotherapy for patients with symptomatic bone-only disease (lymph node <3 cm)
The Panel recommends pembrolizumab for patients with microsatellite instability (MS)I-high or mismatch repair-deficient (dMMR) after progression on other agents listed previously.
The Panel suggests metastasis-directed therapy in the form of radiation or surgical resection after a multidisciplinary evaluation in selected patients with oligometastatic progression.
The Panel recommends using olaparib monotherapy for patients with BRCA1/2 alterations.
The Panel suggests olaparib monotherapy for patients with any of the other HRR alterations.
The Panel recommends using docetaxel chemotherapy, radium 223, or Lu-177-PSMA-617 (for patients with a prostate-specific membrane antigen [PSMA] positive PET scan) for patients regardless of HRR alterations.
The Panel recommends sipuleucel-T or local therapies per prior recommendations for selected patients.
The Panel recommends following prior recommendations for patients with HRR alterations (moderate to low certainty evidence).
The Panel recommends either an ARPI such as abiraterone with prednisone or enzalutamide, or enzalutamide with radium 223 (conditional recommendation), or chemotherapy with cabazitaxel or Lu-177-PSMA-617 for PSMA-positive disease (for patients regardless of HRR alterations).
The Panel recommends Lu-177-PSMA-617 for PSMA-positive disease or radium 223 for PSMA-negative disease or chemotherapy using cabazitaxel.
The Panel recommends olaparib monotherapy for patients with HRR alterations.
The Panel also recommends radium 223 or pembrolizumab for specific situations outlined earlier.
The Panel suggests clinical trials, cabazitaxel + carboplatin, carboplatin monotherapy, best supportive care, and hospice care (evidence not graded for the latter two items) for patients with disease progression despite previously mentioned options.
The Panel recommends utilizing cisplatin or carboplatin plus etoposide for first-line systemic therapy as per Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline.
The Panel suggests carboplatin plus cabazitaxel for patients with small cell neuroendocrine prostate cancer or those with deleterious alterations in two or more of TP53, RB1, and PTEN genes.
The Panel recommends enrollment in clinical trials after progression on platinum-based chemotherapy for eligible patients.
In selected patients, the Panel suggests upfront chemotherapy (carboplatin or cisplatin plus etoposide) with immunotherapy followed by maintenance immunotherapy, lurbinectedin, topotecan, or tarlatamab may be utilized based on extrapolation from studies for small cell lung cancer. Prospective clinical studies for these agents for small cell prostate cancer are lacking, and use of these agents should be considered on a case-by-case basis only.
Assessment of Treatment Response
The Panel recommends using a combination of 1) clinical assessments to evaluate the tolerability of cancer therapy and cancer-related symptoms, 2) blood tests including PSA, CBC with differential, and CMP, and 3) radiologic assessments to determine if patients are benefiting from systemic therapy.
The Panel recommends use of Tc99 bone scan and CT chest, abdomen, and pelvis to define progression for patients with mCRPC (APMR). These radiologic assessments can be performed every 3-6 months or in patients with rising PSA levels and/or evidence of clinical progression.