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Responding to unmet needs for metastatic castration-resistant prostate cancer
Responding to unmet needs for metastatic castration-resistant prostate cancer
Declaration of sponsorship Pfizer

mCRPC: challenges and treatments

Declaration of sponsorship Pfizer
Read time: 40 mins
Last updated:7th Dec 2023
Published:15th Feb 2023
In this section

Metastatic castration-resistant prostate cancer treatment landscape

The continued need for improved mCRPC treatments

Professor Karim Fizazi explains why there is still a pressing need for improved therapies for mCRPC.


Has management of mCRPC improved over time?

Professor Fizazi highlights the key advances over the past 2 decades that have delivered improved outcomes for men with mCRPC.

Metastatic prostate cancer epidemiology

Prostate cancer is one of the most prevalent malignant cancers in the world1.

Many people with newly diagnosed prostate cancer have localised disease, and receive prostatectomy or radiation therapy, followed by androgen-deprivation therapy (ADT). Prostate cancer cells can become resistant to ADT within 2–3 years, although there is variation in this figure in the published literature2-10. Cell malignancy can progress, even when serum testosterone is below castrate level2-10.

Due to this loss of hormone sensitivity, some people CRPC2-10. CRPC can advance to mCRPC, which is associated with high mortality10. mCRPC can develop de novo or from metastatic castration-sensitive prostate cancer (mCSPC)2-10.

Approximately 700,000 men diagnosed with prostate cancer have metastatic disease, accounting for more than 400,000 deaths globally per year11. This mortality is expected to more than double by 204012. However, regional decreases in mortality-to-incidence ratios for prostate cancer (1990–2019) highlight improved outcomes, efficient screening and therapeutic strategies13. Despite the treatment options available for mCRPC, the disease remains incurable.

Figure 1 shows incidence and prevalence data of mCRPC per 100,000 enrolees in a US managed-care, insured population (2009–2018)14.

T1 Prostate Cancer Fig1.png

Figure 1. Incidence and prevalence numbers of mCRPC per 100,000 enrolees, 2009–2018, in a US managed-care, insured population (Adapted14). Incidence of mCRPC was constant over 2009–2018, while prevalence increased.

Brief overview of prostate cancer biology

Some evidence points to persistent inflammation and infection stimulating prostate carcinogenesis through oxidative stress, and production of reactive oxygen species that cause DNA damage and recruitment of mutated cells15-17.

Through inflammation, the prostate is enriched for proliferative luminal epithelial cells that are vulnerable to epigenetic and genomic chromatin alterations, leading to prostatic intraepithelial neoplasia and malignant change15-17.

Prostate cancer largely relies on alterations in the androgen-receptor gene (AR) pathway2-9. mCRPC shows AR changes through amplification, or gain-of-function mutations, increased transcription of AR, or increased AR signalling15-17.

Progression to mCRPC is associated with dysregulation of genes involved in growth control and genetic stability (Figure 2)15-17.

739_ProstateCancer_Tab1_Fig2 revised.png

Figure 2. Somatic mutations, prognostic, and predictive biomarkers in metastatic prostate cancer (Adapted17). AR-V7, AR splice-variant 7; CRPC-NE, castration-resistant neuroendocrine prostate cancer; ctDNA, circulating tumour DNA; CTC, circulating tumour cell; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.

Discovery of molecular markers predictive of treatment responses has stimulated more personalised treatments for mCRPC2-9

The evolving treatment landscape for mCRPC

Primary considerations for specialists managing mCRPC

Professor Axel Merseburger explains that managing mCRPC cannot be reduced to a single variable, but involves consideration of multiple, interacting factors.


Biochemical relapse after local treatment for prostate cancer can progress to metastasis or the development of CRPC2-9. Once mCRPC is identified, there are several first-line treatment options (Figure 3)2-9.

Recommended management options for mCRPC include2-9:

  • The androgen-synthesis inhibitor abiraterone
  • AR-signalling inhibitors (ARSI; also called novel hormonal agents), enzalutamide, apalutamide and darolutamide
  • Cytotoxic chemotherapy agents (docetaxel, cabazitaxel)
  • Radiopharmaceuticals (radium-223, 177Lutetium-PSMA-617)
  • Immunotherapies (sipuleucel-T)

739_ProstateCancer_Tab1_Fig3.png

Figure 3. Treatment landscape for advanced forms of prostate cancer (Adapted18). Some approved treatments refer to the United States only (see ‘US’ in figure). *Olaparib is also approved in the EU for mCRPC combined with abiraterone and prednisone or prednisolone in patients for whom chemotherapy is not clinically indicated19. Yellow boxes show approved treatments, irrespective of molecular profiling. Red boxes refer to biomarker-based treatments, approved only for molecularly-defined subgroups with mCRPC. ADT, androgen deprivation therapy; ARSI, androgen-receptor signalling inhibitor; HR, hormone receptor; mCRPC, metastatic castration-resistant prostate cancer; MMR, mismatch repair deficiency; PARP, poly adenosine diphosphate-ribose polymerase; PSA, prostate-specific antigen.

Delaying disease progression and palliating symptoms are the main clinical goals of mCRPC management2-9. For patients, improving survival is generally the most important goal; however, according to a US patient preference survey, some patients are open to trading 1.9 months of survival time for reduced risk of radiation treatment to manage bone pain, delayed fracture or bone metastasis, or less severe nausea or fatigue20.

ESMO and NCCN treatment guidelines for mCRPCC

Figure 4 shows the timeline of treatments for mCRPC based on the year of the pivotal trial21.

739_ProstateCancer_Tab1_Fig4.png

Figure 4. Timeline of treatments for mCRPC, based on the year of the pivotal clinical trial (Adapted21). *Approval from the European Medicines Agency (EMA) withdrawn, not available in Europe; +Symptomatic, bone only, LN <3 cm, visceral metastases excluded; §EMA approval: BRCA1,2 US Food and Drug Administration (FDA): homologous recombination deficiency (HRD) panel PROFOUND22; rucaparib (US FDA only); **Approved by the FDA, not approved in Europe.

Docetaxel (TAX 327; SWOG 99-16)

Docetaxel improved overall survival (OS) compared with mitoxantrone (18.9 months vs 16.5 months; HR, 0.76; 95% CI, 0.62–0.94; P=0.009), and in combination with estramustine, compared with mitoxantrone (17.5 months vs 15.6 months; HR, 0.8; 95% CI, 0.67–0.97; P=0.02)23,24. In 2004, docetaxel became the standard-of-care first-line treatment for mCRPC23,24. Docetaxel is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for mCRPC25,26.

Cabazitaxel (TROPIC; CARD; FIRSTANA)

In the phase 3 TROPIC trial, cabazitaxel was superior to mitoxantrone for OS in people with mCRPC progressing on, or after, docetaxel (15.1 months vs 12.7 months; HR, 0.7; 95% CI, 0.59–0.83; P<0.0001)27. In the phase 4 CARD trial, the median OS for cabazitaxel was 13.6 months, and 11.0 months with the ARSI (HR, 0.64; 95% CI, 0.46–0.89; P=0.008). In the phase 3 FIRSTANA trial, cabazitaxel did not demonstrate superiority for OS compared with docetaxel in patients with chemotherapy-naive mCRPC28. Cabazitaxel is FDA and EMA indicated for the treatment of mCRPC29,30.

Abiraterone (COU-AA-301; COU-AA-302), enzalutamide (AFFIRM; PREVAIL)

Pivotal phase 3 trials with abiraterone (COU-AA-301; COU-AA-302) and enzalutamide (AFFIRM; PREVAIL) showed improved OS or radiographic progression-free survival (rPFS) for mCRPC following treatment with docetaxel, and in patients naive to docetaxel31-34:

  • COU-AA-301: OS was longer for abiraterone acetate–prednisone than for placebo–prednisone (14.8 months vs 10.9 months; HR, 0.65; 95% CI, 0.54–0.77; P<0.001)31
  • COU-AA-302: Median rPFS was 16.5 months for abiraterone–prednisone and 8.3 months for prednisone alone (HR for abiraterone–prednisone vs prednisone, 0.53; 95% CI, 0.45–0.62; P<0.001). Over a median follow-up period of 22.2 months, OS improved for abiraterone–prednisone (median not reached vs 27.2 months for prednisone alone; HR, 0.75; 95% CI, 0.61–0.93; P=0.01)32
  • AFFIRM: Median OS was 18.4 months (95% CI, 17.3 to not yet reached) for enzalutamide, versus 13.6 months (95% CI, 11.3–15.8) in the placebo group (HR for enzalutamide, 0.63; 95% CI, 0.53–0.75; P<0.001)33
  • PREVAIL: rPFS at 12 months was 65% for enzalutamide and 14% for placebo (81% risk reduction; HR for enzalutamide group, 0.19; 95% CI, 0.15–0.23; P<0.001)34

Abiraterone is FDA and EMA approved for mCRPC35,36.

Radium-223 (ALSYMPCA)

In ALSYMPCA, radium-223 reduced the risk of death by 30% compared with placebo in symptomatic people with mCRPC (predominant bone metastases) who had received, were ineligible to, or had refused to receive docetaxel (HR, 0.7; 95% CI, 0.58–0.83; P<0.001)37. Radium-223 was FDA and EMA approved for mCRPC in 201338,39.

177Lutetium-PSMA-617 (VISION)

177Lutetium-PSMA-617 improved OS in people with prostate-specific membrane antigen (PSMA)-positive mCRPC previously treated with at least one ARSI, and one or two taxane regimens, compared with the protocol that permitted standard care alone (15.3 months vs 11.3 months, HR, 0.62; 95% CI, 0.52–0.74; P<0.001)40. 177Lutetium-PSMA-617 is approved by the FDA and EMA for mCRPC41,42.

Olaparib (PROFOUND)

In the phase 3 PROFOUND study, the poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) olaparib reduced the risk of death by 31% in people with mCRPC who had a gene alteration in BRCA1, BRCA2 or ATM, and whose disease had progressed during previous treatment with enzalutamide or abiraterone (HR, 0.69; 95% CI, 0.50–0.97; P=0.02)22. Olaparib is FDA and EMA indicated for mCRPC19,43.

Talazoparib (TALAPRO-2)

In the phase 3 TALAPRO-2 clinical trial, median rPFS was significantly improved in the talazoparib plus enzalutamide group versus placebo plus enzalutamide group (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P<0.001)44. Talazoparib is approved by the FDA only in combination with enzalutamide for HRR gene-mutated mCRPC45.

Rucaparib (TRITON 2)

The FDA-approved46 PARPi rucaparib was evaluated in the phase 2 TRITON 2 study47. In TRITON 2, rucaparib showed an objective response rate of 43.5% and a prostate-specific antigen (PSA) response rate of 54.8% in 115 people with mCRPC with BRCA1 or BRCA2 mutations who progressed after at least one ARSI and one taxane-based chemotherapy47.

Sipuleucel-T (IMPACT)

Sipuleucel-T, an autologous cellular immunological agent, improved OS compared with placebo in the phase 3 IMPACT study (25.8 months vs 21.7 months; HR, 0.78; 95% CI, 0.61–0.98; P=0.03)48. The EMA withdrew marketing authorisation for sipuleucel-T due to logistical challenges associated with production49. Therefore, sipuleucel-T is not available in Europe and is only approved by the FDA50.

Unmet needs in mCRPC

Unmet needs in metastatic castration-resistant prostate cancer (mCRPC) include no curative treatment, optimising treatment selection, sequencing, and intensification

What are the unmet medical needs for management of mCRPC?

Professor Karim Fizazi (Institut Gustave Roussy; Université Paris-Saclay, France) explains how shifts in the use of prostate cancer medications can create a requirement for additional therapies and outlines which emerging treatment approaches may help to meet this unmet need.

Unmet needs that negatively affect mCRPC outcomes

Professor Axel Merseburger (University Hospital Schleswig-Holstein, Germany) reviews the common unmet patient needs in mCRPC palliative management, with a focus on unmet needs related to treatment.

Unmet patient needs for a given disease or condition reflect several common factors51:

Mortality

A recent study of real-world treatment patterns noted a median overall survival in people with mCRPC of 11.1–19.4 months52. There is no cure for the disease.

Patient quality of life

Important health-related quality of life (HRQoL) issues for people with mCRPC include pain, nausea, vomiting and insomnia53,54. Many assessments used to measure HRQoL in published research were not developed specifically for mCRPC and may not accurately describe symptoms specific to mCRPC. Inconsistent definitions of clinically meaningful differences are evident in the literature54.

Symptom or disease burden

Common patient-reported symptoms for mCRPC include pain, fatigue, and urinary and sexual dysfunction. Patient-reported symptoms are under-recognised in the management of mCRPC55,56.

Treatment side effects

Treatment-related side effects for mCRPC commonly reported by patients include fatigue, hypertension, arthralgia, nausea, diarrhoea and anxiety2-9. Overall, patient-reported outcomes (PRO) are not consistently measured, or adequately reported, in mCRPC treatment monitoring56.

Treatment inconvenience

This factor is a mix of treatment qualities, including treatment invasiveness, frequency and duration51. There are no available data on patient preferences for treatment invasiveness, frequency and duration, and their interaction, in the mCRPC setting. However, people with mCRPC consistently rank treatment effectiveness and delay in time to symptoms, as the most important treatment qualities57.

Selecting the optimal treatments and treatment sequence for a person with mCRPC, in the absence of validated predictive biomarkers, is an unmet need2-9. Sequential use of androgen-receptor signalling inhibitors (ARSI) for mCRPC is limited by cross-resistance between AR-targeted drugs, which further complicates treatment selection and sequencing58.

For people with mCRPC in some lower-income countries, such as in the Middle-East or in Africa, limited access to genetic testing and economic constraints are major unmet needs59

Professor Merseburger examines unmet patient needs in mCRPC

ESMO and NCCN guideline recommendations for mCRPC

Clinical practice guideline recommendations for mCRPC

Professor Merseburger reviews clinical practice guideline (CPG) recommendations for the pharmacological management of mCRPC.

Table 1 describes European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guideline recommendations for mCRPC2-5,60,61.

Table 1. ESMO and NCCN guideline recommendations for metastatic castration-resistant prostate cancer (Adapted2-5,60,61). ADT, androgen-deprivation therapy; AR, androgen-receptor; ChT, chemotherapy; ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; mCRPC, metastatic castration-resistant prostate cancer; PSMA, prostate-specific membrane antigen.

European Society for Medical Oncology (ESMO) recommendations for mCRPC National Comprehensive Cancer Network (NCCN) recommendations for mCRPC
• Abiraterone or enzalutamide [ESMO-MCBS v1.1 score: 4] is advised for asymptomatic or mildly symptomatic ChT-naive mCRPC

• Docetaxel [ESMO-MCBS v1.1 score: 4] is recommended

• In the post-docetaxel setting, abiraterone [ESMO-MCBS v1.1 score: 4], enzalutamide [ESMO-MCBS v1.1 score: 4] or cabazitaxel [ESMOMCBS v1.1 score: 3] are options

• For bone metastases from CRPC at risk for clinically significant skeletal-related events, a bisphosphonate or denosumab is recommended

• Radium-223 [ESMO-MCBS v1.1 score: 5] is advised for bone-predominant, symptomatic mCRPC without visceral metastases

• Radium-223 is not recommended in combination with abiraterone and prednisolone

• Use of a second AR inhibitor (abiraterone after enzalutamide or vice versa) is not advised

• Olaparib is an option after abiraterone, enzalutamide, apalutamide, or darolutamide (with or without prior taxanes) for mCRPC and BRCA1/2 alterations [ESMO-MCBS v1.1 score: 3]​

• In patients who have received abiraterone, apalutamide, darolutamide, or enzalutamide, and docetaxel, patients can receive 177Lu-PSMA-617 (for mCRPC expressing PSMA on positron emission tomography-PSMA and without PSMA non-expressing lesions) [ESMO-MCBS v1.1 score: 4], or cabazitaxel [IESMO-MCBS v1.1 score: 3]

 • Olaparib is advised for mCRPC and a pathogenic mutation (germline and/or somatic) in a homologous recombination repair gene, or in patients who have been treated previously with AR-directed therapy

• Rucaparib is an option for mCRPC and a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic), who have been treated with AR-directed therapy and a taxane-based chemotherapy

• Cabazitaxel starting dose can be 20 mg/m², or 25 mg/m², for progressive mCRPC, despite prior docetaxel chemotherapy

• Patients with asymptomatic or minimally symptomatic mCRPC may consider immunotherapy

• 177Lutetium-PSMA-617 is not recommended in patients with dominant PSMA-negative lesions

• Docetaxel with a concurrent steroid is the advised first-line chemotherapy treatment for symptomatic mCRPC

What guideline recommendations are challenging to apply in clinical practice?

Professor Fizazi identifies recommendations that affect clinical uptake of guidelines in the mCRPC setting.

Do treatment patterns for mCRPC follow guideline recommendations?

One real-world study evaluated country-specific CPGs for advanced prostate cancer and assessed treatment patterns for people with mCRPC in France, Germany, Italy, Spain, the UK and Japan62.

  • Current CPGs for mCRPC advise the first-line androgen-synthesis inhibitor abiraterone, the ARSI enzalutamide, poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) and PARPi combinations (with abiraterone), lutetium-prostate-specific membrane antigen (PSMA) therapy, radium-223, and chemotherapy (docetaxel, cabazitaxel), all with classical androgen-deprivation therapy (ADT) as backbone treatment2-9,62
  • The most common first- to second-line treatment sequence for mCRPC in the analysed countries was ARSI, then chemotherapy62

The study authors found that treatment patterns for mCRPC were largely in accordance with country CPGs, and were consistent with the available treatment options that were reimbursed62. However, following approval of more effective pharmaceutical treatments for mCRPC, there is a demand for regular updates of international CPGs on treatments for advanced prostate cancer. Patients and healthcare professionals can find it difficult staying informed about treatment innovations for mCRPC21,63.

Factors that obstruct clinician adherence to oncology guidelines

No published study has investigated level of clinician adherence to CPGs in mCRPC management. However, a systematic review evaluated clinician attitudes and perceived barriers, or facilitators, to cancer treatment CPG adherence64. Clinician adherence to oncology CPGs is obstructed by64:

Concerns about CPG content and currency

Some CPGs are not consistently applicable to specific oncology settings, are unclear, hard to implement, or read.

Concerns about conflicting recommendations reported across CPGs

Clinicians feel uncertain in their decision-making when recommendations in different CPGs are not consistent with each other.

Concerns about restricted autonomy or authority

Some clinicians feel CPGs limit autonomous clinical judgement. Clinical equipoise or clinical habits that diverge from CPG recommendations are potential barriers to CPG adherence.

Organisational concerns

Organisational barriers to CPG adherence include restricted access to treatment facilities or services; treatment referral that is slow, unreliable, or complex; a lack of leadership.

Professor Merseburger offers his view on the barriers preventing clinical uptake of guideline recommendations for mCRPC

Clinical practice guidelines do not replace clinical decision-making

CPG recommendations are not absolute, but provisional under the conditions described in each CPG. CPG updates normally reflect new knowledge about disease management, which is amenable to refinement or replacement2-9,62. Thus, CPGs do not supplant clinical decision-making in individual cases. Implementation of any CPG recommendation does not assure a successful clinical outcome. Available resources and patient tolerances, needs and preferences, should be considered along with CPGs2-9,62.

Precision medicine for mCRPC

Using knowledge of altered genes or pathways in metastatic prostate cancer (mCRPC), precision medicine could provide management options for patients with mCRPC

Is precision oncology benefiting the mCRPC treatment landscape?

Professor Neeraj Agarwal charts the evolution of precision medicine for mCRPC to date and rounds up the treatments under investigation.

Precision medicine in mCRPC

Genomic alterations tend to be heterogeneous in mCRPC, and show specific effects in mCRPC progression and resistance to treatments18,65. Through understanding how specific genes or pathways are altered in an individual with mCRPC (Figure 5), precision medicine could advise on suitable diagnostic tests, and treatment approaches, for patients18,65.

T1 Prostate Cancer Fig5.png

Figure 5. Precision medicine in metastatic castration-resistant prostate cancer (Adapted65). A, androgen; AR, androgen receptor; ARm, mutant AR; ARV, AR splice-variant; CDK, cyclin-dependent kinase; PARPi, poly adenosine diphosphate-ribose polymerase inhibitor.

Altered androgen-receptor signalling in mCRPC

Genomic alterations that develop in 50–70% of people with mCRPC involve androgen-receptor (AR) amplification, AR activating mutations (L702H, W742C, F877L, T878A) and AR structural changes, (deletion, duplication, inversion, translocation). These alterations reactivate AR signalling (Figure 6)65,66.

Figure_6_739LO4.png

Figure 6. Altered androgen-receptor signalling in metastatic castration-resistant prostate cancer (Adapted65). A, androgen; ABI, abiraterone; AR, androgen receptor; ARm, mutant AR; ENZA, enzalutamide; mut, mutation.

Clinical implications of altered androgen-receptor signalling in mCRPC

Alterations in AR signalling can lead to resistance to first-line AR-based treatments for mCRPC65. For example, sequential treatment with the androgen-synthesis inhibitor abiraterone followed by the ARSI enzalutamide is not universally supported for mCRPC:

  • Abiraterone followed by enzalutamide (or vice versa) can lead to prostate-specific antigen (PSA) response rates <30%, possibly indicating treatment cross-resistance67-69
  • In the phase 4 PLATO trial, adding abiraterone following enzalutamide resistance showed no differences in progression-free survival (PFS) between the combination group, and in patients switching to abiraterone monotherapy70
  • In the ALLIANCE trial, combining abiraterone and enzalutamide revealed no differences in overall survival (OS) compared with enzalutamide alone71

These data suggest that AR-based resistance mechanisms overlap in mCRPC, such that cross-treatment resistance remains unchanged following treatment with an androgen-receptor signalling inhibitor (ARSI)18,65. As just one potential solution to persistent AR-driven disease, high-dose testosterone or ‘bipolar androgen therapy’ (BAT) could restore responses to enzalutamide72. Other treatment solutions are under investigation18,65.

Homozygous mutation of 1245 A>C HSD3B1 predicted decreased metastasis-free survival and OS following prostatectomy, and decreased PFS in patients on androgen-deprivation therapy (ADT)73,74. HSD3B1 could aid in stratifying patients for treatment intensification by biomarking individuals resistant to ADT18,65. Identification of biomarkers associated with the ARSI response could guide treatment selection in mCRPC75. In people with mCRPC receiving abiraterone, point mutations involving SPOP were associated with improved OS, compared with those with wild-type SPOP75.

Changes in the PTEN-PI3K-AKT pathway in mCRPC

Figure 7 shows dysregulated PI3K-AKT signalling in mCRPC. The tumour suppressor PTEN is deleted in ~50% of mCRPC tumours76. Alterations in PIK3CA, PIK3CB, PIK3R1 and AKT1 are less commonly observed18,65.

T1 Prostate Cancer Fig7 revised.png

Figure 7. Dysfunctional PI3K-AKT signalling in metastatic castration-resistant prostate cancer (Adapted65). Note: abiraterone acetate is converted in vivo to abiraterone, an androgen-synthesis inhibitor77,78. A, androgen; ABI, abiraterone; AKT, protein kinase B; AKTI, AKT inhibitor; FKBP5, FK506-binding protein 5; PHLPP, PH domain leucine-rich repeat protein phosphatase; Ptdlns(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate; Ptdlns(4,5)P2, phosphatidylinositol 4,5-bisphosphate; RTK, receptor-tyrosine kinase.

Clinical implications of altered PTEN-PI3K-AKT in mCRPC

Treatments targeting alterations in PIK3CA, PIK3CB, PIK3R1 and AKT1 could benefit people with mCRPC18,65.

PTEN deletion is linked to resistance to ARSI treatments79. For example, in people with mCRPC receiving abiraterone after docetaxel, in whom 40% had no PTEN tumour expression, an association was found between PTEN deletion and shorter OS (14 months compared with 21 months), and time using abiraterone79.

The phase 3 IPATential150 trial is investigating ipatasertib (an inhibitor of protein kinase B [AKT]) plus abiraterone and prednisone/prednisolone, compared with placebo plus abiraterone, and prednisone/prednisolone in mCRPC. A primary outcome is radiographic PFS (rPFS) in patients with PTEN loss through immunohistochemistry compared with the intent-to-treat population80. In the 521 (47%) patients with tumours and PTEN loss, median rPFS was 16.5 months (95% CI, 13.9–17.0) in the placebo–abiraterone group, and 18.5 months (95% CI, 16.3–22.1) in the ipatasertib–abiraterone group (HR, 0.77; 95% CI, 0.61–0.98; P=0.034). In the intent-to-treat population, median PFS was 16.6 months (95% CI, 15.6–19.1) in the placebo–abiraterone group and 19.2 months (16.5–22.3) in the ipatasertib–abiraterone group (HR, 0.84; 95% CI, 0.71–0.99; P=0.043)81.

DNA repair in mCRPC

Germline or somatic mutations involving DNA repair genes (including BRCA1, BRCA2, ATM, MSH2) are evident in 20% of mCRPC (Figure 8)65,82.

T1 Prostate Cancer Fig8.png

Figure 8. DNA repair pathway in metastatic castration-resistant prostate cancer (Adapted65). CDK, cyclin-dependent kinase; DSB, double-strand breaks; PARPI, poly adenosine diphosphate-ribose polymerase inhibitor; RNA Pol II, RNA polymerase II.

Clinical implications of altered DNA repair in mCRPC

Clinical practice guidelines now advise germline testing for all patients with mCRPC2-9,62.

Loss of homologous recombination genes is associated with inhibition of poly adenosine diphosphate-ribose polymerase (PARP), or a DNA-damaging treatment, such as platinum chemotherapy, through the mechanism called ‘synthetic lethality’83. The phase 3 PROFOUND trial investigated the PARP inhibitor (PARPi) olaparib in men with mCRPC who had progressed while receiving a new hormonal agent, such as enzalutamide or abiraterone, and who had a qualifying alteration in prespecified genes with a role in homologous recombination repair (HRR)22. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2 or ATM; cohort B (142 patients) had alterations in any of 12 prespecified genes22.

In cohort A, imaging-based PFS was significantly longer for olaparib than in the control group (median, 7.4 months vs 3.6 months; HR 0.34; 95% CI, 0.25–0.47; P<0.001). The median OS in cohort A was 18.5 months for olaparib and 15.1 months for the control group22.

Olaparib was approved for treatment of mCRPC as monotherapy in the presence of germline or somatic BRCA1/2 mutations after progression on a new hormonal agent, or combined with abiraterone and prednisone or prednisolone when chemotherapy is not clinically indicated19,43.

Data on which genes to test for mCRPC, and which alterations respond best to PARPI or platinum chemotherapy, are needed18,65

An explanation of treatment resistance in the mCRPC setting would be optimal. This knowledge would include, for example, identification in patients who develop resistance and, of those, who would benefit from sequential treatment with PARPi after platinum chemotherapy (or vice versa)84.

CDK12 inactivation (Figure 8) could define a specific class of mCRPC, which may benefit from immune checkpoint immunotherapy85.

More about first-line treatments for people with mCRPC with or without DNA-damage repair alterations

Cell-cycle dysfunction in mCRPC

Genomic changes leading to dysfunction of the cell-cycle regulators RB1 and/or cyclin-dependent kinases (CDK) are present in up to 25% of patients76,86.

RB1 loss is observed in approximately 10% of people with mCRPC and is associated with poor prognoses87. Alterations in CDK have been documented in 3–7% of people with mCRPC88.

RB1 restrains E2F from driving cyclins and CDKs to advance to S phase; loss of RB1, or gain of CDKs, results in uncontrolled cellular proliferation cellular adaptations that can grow cancer cells (Figure 9)65.

Figure_9_739LO3.png

Figure 9. Dysfunctional cell cycle in metastatic castration-resistant prostate cancer (Adapted65). CDK, cyclin-dependent kinase.

Clinical implications of altered cell cycle in mCRPC

Cell-cycle inhibitors target the molecular components that regulate DNA replication. They also coordinate the DNA damage repair (DDR) network, resulting in cell cycle arrest and cell death89. Small molecule-kinase inhibitors are under investigation targeting key proteins recruited in the four phases of the cell cycle: G1 (gap), S (synthesis), G2 (gap), and M (mitosis)89:

  • G1: palbociclib90, ribociclib91, AZD-5363 (completed)92, ipatasertib80
  • S: M-662093, prexasertib94
  • G2: adavosertib95,96
  • M: alisertib97

Future innovations in precision medicine for mCRPC

Whole-genome sequencing

Targeted and whole-exome sequencing studies have identified recurrent alterations in mCRPC involving coding genes18,65.

Whole-genome sequencing (WGS) could describe the full genomic landscape of structural variations in mCRPC18,65. WGS shows that 70–87% of mCRPC tumours amplify an upstream enhancer of the AR gene, resulting in AR overexpression, and could contribute to ARSI treatment resistance16,98,99.

Liquid biopsy for mCRPC

Liquid biopsy could capture the relative contribution of different anatomical sites of metastases in the bloodstream, providing a non-invasive and safer serial tumour sampling in mCRPC100.

Meeting unmet needs using precision oncology for metastatic prostate cancer

Table 2. Strategies to meet unmet needs using precision oncology for metastatic prostate cancer18,65.

Table 2. Strategies to meet unmet needs using precision oncology for metastatic prostate cancer (Adapted18,65). CT, computerised tomography; PSMA-PET, prostate-specific membrane antigen positron-emission tomography.

Unmet need Strategies to meet the unmet need
Ability to procure tumour material for molecular profiling • Develop guidelines for improving biopsy yield, amenable to clinical practice

• Teaching videos on current best practices, and emerging techniques for bone biopsy and procurement

• Next-generation imaging using higher resolution for functional assessments of the tumour
Being able to explain tumour heterogeneity • Advanced imaging assays for selecting lesions with resistance to systemic agents for re-biopsy (PSMA-PET/CT)
Ability to integrate clinical features and genomic alterations for biomarker identification • Tools to accumulate and visualise clinical-genomic datasets (cBioPortal for Cancer Genomics; AACR Genomics Evidence Neoplasia Information Exchange [GENIE])

• Integration of genomic data into electronic medical records

• Machine learning and Artificial Intelligence

• Standards for the transfer of genomic results

• Ethics for accessing and use of human data
Skill in understanding the impact of genomics in diverse groups • Partnering with patients and advocacy groups

• Count Me In Project (https://mpcproject.org)

• IRONMAN global population-based registry
Correctly matching patients to treatments or clinical trials • Infrastructure for patients to identify and receive matched treatments (approved or unapproved)

• Tools: clinicaltrials.gov database, local molecular academic tumour boards, commercially-available molecular testing reports that offer access to ordering clinicians

Responding to unmet treatment needs for mCRPC

To help meet unmet treatment needs for mCRPC, novel first-line pharmaceutical strategies, including new therapeutic combinations, are under investigation

Can knowledge of treatment mechanism of action improve mCRPC management?

Professor Karim Fizazi describes target pathways, beyond the androgen receptor, that can guide the choice of therapy for men with mCRPC.

A new standard-of-care for mCRPC?

In advanced prostate cancer, there is an unmet need for new, alternative treatments that could overcome treatment resistance. In the mCRPC setting, several investigational treatments have emerged as candidate first-line treatments, and could become the next-generation standard-of-care (SOC) (Table 3)21,63.

Table 3. Ongoing Phase 3 clinical trials in 2022 for metastatic castration-resistant prostate cancer (Adapted21).

NCT number (trial name) Setting Treatment arms Results
NCT03072238 (IPATential150) mCRPC
1st-line		 ADT + abiraterone + ipatasertib vs ADT + abiraterone + placebo​ rPFS PTEN-loss by IHC: 18.5 months vs 16.5 months, HR 0.77; 95% CI, 0.61–0.98; P=0.034
rPFS intention-to-treat population: 19.2 months vs 16.6 months, HR 0.84; 95% CI, 0.71– 0.99, P=0.043
NCT03732820
(PROPEL)		 mCRPC
1st-line
Prior docetaxel in mHSPC allowed
Prior ARSI in mHSPC or nmCRPC allowed if stopped ≥12 months prior		 ADT + abiraterone + olaparib vs ADT + abiraterone + placebo​ rPFS investigator assessed: 24.8 months vs 16.6 months, HR 0.66; 95% CI, 0.54–0.81, P<0.0001
rPFS blinded independent central review: 27.6 months vs 16.4 months, HR 0.61; 95% CI, 0.49–0.74, P<0.0001
OS: immature data (23% events), HR 0.86; 95% CI, 0.66–1.12 ORR: 58% vs 48%
NCT03748641 (MAGNITUDE) mCRPC
1st-line HRR± vs HRR-
prospectively assessed
Prior docetaxel in mHSPC allowed
Prior ARSI in mHSPC or nmCRPC allowed if stopped ≥12 months; prior abiraterone allowed if ≤4 months		 ADT + abiraterone + niraparib vs ADT + abiraterone + placebo​ rPFS: central independent blinded review HRR-: stopped enrollment after futility analysis (defined HR > 1.0) after 233 patients, HR 1.09 HRR±: 16.5 months vs 13.7 months, HR 0.75; 95% CI, 0.57–0.97; P<0.0001
OS: immature data (27% events)
RR: 2.13 ORR: 60% vs 28%
NCT02257736
(ACIS)		 mCRPC
1st-line		 ADT + abiraterone + apalutamide vs ADT + abiraterone + placebo​ rPFS (median follow-up 25.7 months): 22.6 months vs 16.6 months, HR 0.69; 95% CI, 0.58–0.83; P<0.0001
rPFS updated analysis (median follow-up 54.8 months):
24.0 months vs 16.6 months,
HR 0.70; 95% CI, 0.60–0.83; P<0.0001

ADT, androgen-deprivation therapy; ARSI, androgen-receptor signalling inhibitor; CHT, chemotherapy; CI, confidence interval; HR, hazard ratio; HRR, homologous recombination repair; IHC, immunohistochemistry; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; ORR, overall response rate; OS, overall survival; PTEN, phosphatase and tensin homolog; rPFS, radiographic progression-free survival; RR, relative risk.

Combination treatments for mCRPC

MAGNITUDE

In the phase 3 MAGNITUDE trial, the combination of abiraterone (an androgen-synthesis inhibitor) and niraparib (an inhibitor of poly adenosine diphosphate-ribose polymerase [PARP]) versus abiraterone alone was evaluated in people with mCRPC, and with or without homologous recombination repair (HRR) gene alterations. There was no benefit in radiological progression-free survival (rPFS) in patients without HRR alterations (experimental arm). In patients with HRR mutations, abiraterone plus niraparib showed a statistically significant improvement in rPFS (16.5 months vs 13.7 months; HR, 0.73; 95% CI, 0.56–0.96; P=0.0217)101.

The final 3-year update and analysis favoured niraparib with abiraterone acetate plus prednisone versus placebo with abiraterone acetate plus prednisone for102:

  • Overall survival (OS; multivariate analysis) (HR, 0.66; 95% CI, 0.46–0.95; P=0.02)
  • Time to symptomatic progression and time to cytotoxic chemotherapy
  • Time to worst pain progression and time to pain interference progression

PROPEL

In the phase 3 PROPEL trial, the combination of abiraterone and olaparib improved rPFS compared with abiraterone alone (27.6 months vs 16.4 months; HR 0.61; 95% CI, 0.49–0.74; P<0.0001), independently of HRR status. If these data are confirmed in the OS analyses, the study authors suggest that this combination could be a potential first-line SOC treatment for mCRPC103.

Post hoc analyses for men with non-BRCA mCRPC showed better median rPFS (24.1 months vs 19 months; HR, 0.76; 95% CI, 0.61–0.94) and median OS (39.6 months vs 38.0 months; HR, 0.91; 95% CI, 0.73–1.13) for abiraterone−olaparib versus placebo−abiraterone104.

TALAPRO 2, TALAPRO 3

TALAPRO-2 is a phase 3, two-part clinical trial that evaluated the efficacy and safety of talazoparib plus enzalutamide as first-line treatment for mCRPC (with or without DDR/HRR alterations)105. The primary endpoint was rPFS.

TALAPRO-2, Part 1

In Part 1 of TALAPRO-2, treatment-emergent adverse events (TEAE) that led to talazoparib dose reduction were reported in six patients (46.2%) and no patients in the talazoparib–enzalutamide 1 mg once-daily (QD) and talazoparib–enzalutamide 0.5 mg QD cohorts, respectively. In the 1 mg QD cohort, target safety events showed for seven patients (53.8%) compared with no patients in the 0.5 mg QD cohort. Pharmacokinetic data showed that enzalutamide increased talazoparib exposure105.

Based on these safety data, talazoparib 0.5 mg QD plus enzalutamide 160 mg QD is the starting dose for TALAPRO-2, Part 2. The primary endpoint was rPFS44.

TALAPRO-2, Part 2

Median rPFS was significantly improved in the talazoparib–enzalutamide versus placebo–enzalutamide arm (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P<0.001)44

rPFS was significantly improved in HRR-deficient (HR, 0.46; 95% CI, 0.30–0.70; P<0.001), HRR-non-deficient or unknown (HR, 0.70; 95% CI, 0.54–0.89; P=0.004), and HRR-non-deficient people with mCRPC by tumour tissue testing (HR, 0.66; 95% CI, 0.49–0.91; P=0.009) for talazoparib–enzalutamide versus placebo–enzalutamide44.

Talazoparib–enzalutamide improved secondary endpoints objective response rate (ORR), prolonged time to PSA progression; time to initiation of cytotoxic chemotherapy; and time to progression on first subsequent antineoplastic therapy or death (PFS2), versus placebo–enzalutamide, in HRR+ and HRR-/unknown subgroups106.

The most common TEAEs for talazoparib were anaemia, neutropenia and fatigue; the most common grade 3–4 TEAE was anaemia, which improved after dose reduction; 33 (8%) of 398 patients discontinued talazoparib because of anaemia44.

Longer rPFS was associated with higher average talazoparib concentrations (Cavg,t), which supports using 0.5 mg QD (with enzalutamide) for mCRPC107.

Exploratory germline versus somatic origin of HRR gene alterations found that rPFS was comparable for patients with germline and somatic alterations for talazoparib–enzalutamide, but shorter for gHRRm in placebo–enzalutamide, which suggests a poor prognosis subgroup that could be prioritised for talazoparib–enzalutamide treatment108

TALAPRO-3

TALAPRO-3 is an ongoing phase 3, randomised study of enzalutamide plus talazoparib, versus placebo plus enzalutamide, in patients with DDR/HRR gene altered metastatic castration-sensitive prostate cancer (mCSPC)109. The primary endpoint is rPFS109. TALAPRO-3 data are expected for publication on clinical trial registries in 2024.

RAMP; CASPAR

In the phase 1b RAMP study, rucaparib plus enzalutamide induced a decline in PSA in three-fourths of participants (6 of 8 patients), and a PSA response in half (4 of 8 patients)110.

Genomic data were assessed for three-fourths of the participants, who had received previous AR-directed therapy. Of the 4/6 participants who had one or more somatic AR alterations, three had a PSA decline with the combination rucaparib plus enzalutamide.

The ongoing phase 3 CASPAR trial is investigating rucaparib plus enzalutamide in biomarker-unselected people with mCRPC111. Co-primary endpoints are rPFS and OS111.

Download this infographic illustrating the link between genomic and transcriptomic alterations in mCRPC, and potential treatment targets

177Lu-PSMA-617

VISION

Prostate-specific membrane antigen (PSMA) is expressed in mCRPC112. In people with mCRPC, metastatic lesions are PSMA-positive113, and expression is correlated with reduced survival114. 177Lu-PSMA-617, a radioligand therapy, sends beta-particle radiation to PSMA-expressing cells115.

The phase 3 VISION trial investigated 177Lu-PSMA-617 in people with mCRPC previously treated with at least one ARSI, and one or two taxane regimens, and who had PSMA-positive gallium-68 (68Ga)-labelled PSMA-11 positron-emission tomography (PET). 177Lu-PSMA-617 and SOC significantly prolonged rPFS compared with SOC alone (median 8.7 months vs 3.4 months; HR, 0.40; 99.2% CI, 0.29–0.57; P<0.001), and OS (median 15.3 months vs 11.3 months; HR 0.62; 95% CI, 0.52–0.74; P<0.001)116.

177Lu-PSMA-617 plus SOC delayed time to worsening health-related quality of life, pain and time to skeletal events compared with SOC117.

TheraP

A direct comparison between 177Lu-PSMA-617 and cabazitaxel was conducted in TheraP118. In this phase 2 trial, 177Lu-PSMA-617 led to a higher PSA response (65% vs 37%; P<0.0001), and fewer grade 3 or 4 adverse events (33% vs 53%). TheraP data presented at the 2022 ASCO Annual Meeting revealed no difference in OS between 177Lu-PSMA-617 and cabazitaxel (HR, 0.97; 95% CI, 0.7–1.4; P=0.99)119.

Patient access to 177Lu-PSMA-617

A factor that could affect patient access to 177Lu-PSMA-617 is its radioactive component. For example, a substance containing radioactive material should be administered by a person well-trained in handling such materials (e.g., typically staff from a hospital’s nuclear medicine or radiation oncology departments)120. Smaller hospitals or clinics may not have such expertise in-house.

Clinical validation of PSMA uptake with certain standardised uptake value (SUV) cut-offs, could aid in selecting patients for 177Lu-PSMA-617119,121. A mean SUV of >10 (all lesions) shows higher odds of PSA-50 response rate to 177Lu-PSMA-617 (TheraP); patients with the highest quartile of SUV (approximately >10) had the longest rPFS and OS (VISION)119.

The American Society of Clinical Oncology (ASCO) recommends 177Lu-PSMA-617 for patients with PSMA-PET/CT-positive mCRPC, who have progressed on one prior line of ARSI, and at least one line of chemotherapy122

Watch Professor Merseburger discuss investigational treatments that could meet unmet needs in mCRPC

Treatment sequencing and intensification for mCRPC

Current clinical practice guidelines for metastatic castration-resistant prostate cancer (mCRPC) advise first-line androgen-receptor signalling inhibitor (ARSI) followed by chemotherapy as the preferred treatment sequence2-9. However, how can individual treatments for mCRPC be best used? Is there an optimal treatment sequence or intensification? There is a lack of evidence comparing the different treatment options for mCRPC, especially head-to-head clinical trial evidence. This deficit can increase clinical uncertainty123,124.

In clinical practice, ideal treatment decision-making for mCRPC relies on evaluation of patient health, comorbidities, degree of frailty, previous treatments (efficacy, toxicity), patient preferences and the availability of clinical trials123.

A speculative mCRPC treatment algorithm (sequencing and intensification), encompassing four possible scenarios, has been proposed (Figure 11)124.

739_ProstateCancer_Tab1_Fig12ab.png

739_ProstateCancer_Tab1_Fig12cd.png

Figure 11. Proposed treatment algorithm (sequencing and intensification) for metastatic castration-resistant prostate cancer (Adapted124). *Off-label use. #Only in symptomatic patients with exclusively bone metastases. ¶Only in patients with mutations in DNA damage repair (DDR) genes. †Off-label use only in patients with prostate-specific membrane antigen- positron emission tomography (PSMA-PET)-positive disease. ADT, androgen-deprivation therapy; ARSI, androgen receptor-signalling inhibitor; CABA, cabazitaxel; Lu: 177lutetium-PSMA-617; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; mPC, metastatic prostate cancer; PARPi, poly adenosine diphosphate-ribose polymerase inhibitor; Ra, radium-223.

Scenario 1

For progression following ADT monotherapy, docetaxel or ARSIs are an option, and abiraterone + PARPI can be considered if a DDR gene mutation is detected. Receipt of abiraterone + PARPI as first-line treatment should receive second-line docetaxel, while cabazitaxel, radium-223 and 177lutetium-PSMA-617, should be in subsequent lines124.

Scenario 2

ARSI is a first-line option for mCRPC patients progressed after docetaxel in the mHSPC setting. Cabazitaxel is a consideration for patients with poor prognostic factors. In case of DDR mutations in mCRPC, abiraterone plus PARPI as first-line can be considered124.

Scenario 3

For patients treated with apalutamide in early mCRPC, sequential use of ARSIs can be considered124.

Scenario 4

Cabazitaxel is an option in people with mCRPC and good performance status. In patients with symptomatic bone-only disease, treatment with radium-223 is recommended; in patients with DDR mutations, olaparib is a potential first choice; patients with high PSMA expression on PSMA-PET could receive 177Lu-PSMA-617124.

In the PEACE-1125 and ARASENS125 trials, >45% of patients treated with triple therapy received at least a second ARSI in the sequence. Treatment with ARSIs is therefore an option for asymptomatic patients with mildly progressive mCRPC124.

Although broad guideline recommendations for treatment sequencing are possible in the mCRPC setting, these must be tailored to the individual2-9

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