mCRPC: Challenges and treatments

The continuing need for improved mCRPC treatments

Professor Karim Fizazi (Institut Gustave Roussy, Villejuif, France) explains why there is still a pressing need for improved therapies for mCRPC. View transcript.

Has management of mCRPC improved over time?

Professor Fizazi highlights how mCRPC treatments have “dramatically evolved” in the past 20 years and improved outcomes for men with mCRPC. View transcript.

Metastatic prostate cancer epidemiology

Prostate cancer is one of the most prevalent malignant cancers in the world.¹

Many people with newly diagnosed prostate cancer have localized 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 literature.^2-10 Cell malignancy can progress, even when serum testosterone is below castrate level.^2-10

Because of this loss of hormone sensitivity, some people develop CRPC^2-10. CRPC can advance to mCRPC, which is associated with high mortality.¹⁰ 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 year.¹¹ This mortality is expected to more than double by 2040.¹² However, regional decreases in mortality-to-incidence ratios for prostate cancer (1990–2019) highlight improved outcomes, efficient screening, and therapeutic strategies.¹³ Despite the treatment options available for mCRPC, the disease remains incurable.

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

Figure 1. Incidence and prevalence of metastatic castration-resistant prostate cancer (mCRPC) per 100,000 enrollees, 2009–2018, in a US managed-care, insured population.¹⁴ Reproduced from Wallace et al.¹⁴ with permission from Springer Nature. Incidence of mCRPC was relatively constant between 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 cells.^15-17

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 change.^15-17

Prostate cancer largely relies on alterations in the androgen receptor gene (AR) pathway.^2-9 mCRPC shows AR changes through amplification or gain-of-function mutations, increased transcription of AR, or increased AR signaling.^15-17

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

Figure 2. Somatic mutations, prognostic, and predictive biomarkers in metastatic prostate cancer.¹⁷ Reproduced from Sandhu et al.¹⁷ with permission from Elsevier. AR-V7, AR splice-variant 7; CRPC-NE, castration-resistant neuroendocrine prostate cancer; ctDNA, circulating tumor DNA; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.

Discovery of molecular markers predictive of treatment responses has stimulated more personalized treatments for mCRPC^2-9

The evolving treatment landscape for mCRPC

What key factors influence management of mCRPC? Professor Axel Merseburger (University Hospital Schleswig-Holstein, Campus Lübeck, Germany) notes multiple interacting factors are involved. View transcript.

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

Figure 3. Treatment landscape for advanced prostate cancer.¹⁸ Reproduced from Mateo et al.¹⁸ with permission from Springer Nature. Some approved treatments refer to the USA only (see “USA” 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 indicated.¹⁹ 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 signaling inhibitor; HR, hormone receptor; mCRPC, metastatic castration-resistant prostate cancer; MMR, mismatch repair deficiency; PARP, poly adenosine diphosphate-ribose polymerase; PSA, prostate-specific antigen.

Recommended management options for mCRPC include:^2-9

• The androgen-synthesis inhibitor abiraterone
• AR-signaling 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)

The main clinical goals of mCRPC management are to delay disease progression and palliate symptoms.^2-9 While extending overall survival (OS) is typically the priority for patients with mCRPC, a US patient preference survey revealed that some patients are willing to forgo 1.9 months of OS for elimination of moderate nausea and 3.3 months of OS for a reduction in fatigue from severe to mild.²⁰

ESMO and NCCN guidelines for mCRPC

Figure 4 shows a timeline of treatments for mCRPC based on the year of the pivotal trial.²¹

Figure 4. Timeline of treatments for mCRPC, based on the year of the pivotal clinical trial. Image licensed under CC-BY-NC 3.0 from Turco et al.²¹ *Approval from the European Medicines Agency (EMA) withdrawn; not available in Europe.^{22 †}Symptomatic, bone only, LN <3 cm, visceral metastases excluded. ^‡Olaparib was approved for 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 indicated.^19,23

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).^24,25 Grade 3 or 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common in patients on docetaxel and estramustine than patients on mitoxantrone and prednisone.²⁵ In 2004, docetaxel became the standard-of-care first-line treatment for mCRPC.^24,25 Docetaxel is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for mCRPC.^26,27

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). The most common grade ≥3 adverse events (AE) were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhea (23 [6%] vs one [<1%]).²⁸

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). AE of grade ≥3 occurred in 56.3% of patients on cabazitaxel, and in 52.4% on an ARSI.²⁹ In the phase 3 FIRSTANA trial, cabazitaxel did not demonstrate superiority for OS compared with docetaxel in patients with chemotherapy-naive mCRPC. Rates of grade 3 or 4 treatment-emergent adverse events (TEAE) were 41.2%, 60.1%, and 46.0% for cabazitaxel C20, C25, and D75, respectively.³⁰ Cabazitaxel is FDA and EMA indicated for the treatment of mCRPC.^31,32

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 docetaxel:^33-36

• COU-AA-301: OS was longer for abiraterone acetate–prednisone than for placebo–prednisone (14.8months vs 10.9 months; HR, 0.65; 95% CI, 0.54–0.77; P<0.001). Fluid retention, hypertension, and hypokalemia were more frequent for abiraterone acetate–prednisone than placebo–prednisone.³³
• COU-AA-302: Median rPFS was 16.5months 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). Grade 3 or 4 AEs and abnormalities on liver-function testing were more common with abiraterone–prednisone.³⁴
• AFFIRM: Median OS was 18.4months (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). Rates of fatigue, diarrhea, and hot flashes were higher for enzalutamide.³⁵
• PREVAIL: rPFS at 12months 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). Fatigue and hypertension were the most common AEs associated with enzalutamide.³⁶

Abiraterone is FDA and EMA approved for mCRPC.^37,38

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). Radium-223 was associated with lower myelosuppression rates and fewer AEs than placebo.³⁹ Radium-223 was FDA and EMA approved for mCRPC in 2013.^40,41

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). AE rates of grade ≥3 were higher with ¹⁷⁷Lu-PSMA-617 than without (52.7% vs 38.0%); quality of life was not adversely affected.^{42 177}Lutetium-PSMA-617 is approved by the FDA and EMA for mCRPC.^43,44

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). Anemia and nausea were the most common AEs in patients receiving olaparib.⁴⁵ Olaparib is FDA and EMA indicated for mCRPC.^19,23

Talazoparib (TALAPRO-2, 3)

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). In the talazoparib group, the most common TEAEs were anemia, neutropenia, and fatigue; the most common grade 3–4 AE was anemia (185 [46%] of 398 patients); 33 (8%) of 398 patients discontinued talazoparib due to anemia.⁴⁶ Talazoparib is approved by the FDA only in combination with enzalutamide for HRR gene-mutated mCRPC, and by the EMA for patients with mCRPC in whom chemotherapy is not clinically indicated.^47,48 TALAPRO-3 data are expected for publication on clinical trial registries later in 2024.⁴⁹

Rucaparib (TRITON 2)

The approved PARPi rucaparib was evaluated in the phase 2 TRITON 2 study.^50-52 In TRITON  2, rucaparib showed an objective response rate of 43.5% and a prostate-specific antigen 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 chemotherapy. The most frequent grade ≥3 TEAE was anemia (25.2%; 29 of 115 patients). ⁵²

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). AE were more frequently observed for sipuleucel-T than placebo, including headache, chills, and fever.⁵³

At the request of the manufacturer, EMA withdrew marketing authorization for sipuleucel-T because of logistical challenges associated with production.²² Therefore, sipuleucel-T is not available in Europe and is only approved by the FDA.⁵⁴

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

What are the unmet medical needs for management of mCRPC?

Professor Karim Fizazi (Institut Gustave Roussy, Villejuif, France) describes some investigational treatments that may address unmet needs in mCRPC management. View transcript.

Treatment strategies that can address unmet needs for mCRPC

“We have strategies that could help to overcome those unmet needs in mCRPC.” Professor Axel Merseburger (University Hospital Schleswig-Holstein, Campus Lübeck, Germany) offers guidance for balancing considerations around treatment selection in mCRPC. View transcript.

Unmet patient needs for a given disease or condition reflect several common factors:⁵⁵

Mortality

A recent study of real-world treatment patterns noted a median overall survival in people with mCRPC of 11.1–19.4 months.⁵⁶ 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 insomnia.^57,58 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 literature.⁵⁸

Symptom or disease burden

Common patient-reported symptoms for mCRPC include pain, fatigue, urinary and sexual dysfunction. Patient-reported symptoms are under-recognized in the management of mCRPC.^59,60

Treatment side effects

Treatment-related side effects for mCRPC commonly reported by patients include fatigue, hypertension, arthralgia, nausea, diarrhea, and anxiety.^2-9 Overall, patient-reported outcomes are not consistently measured, or adequately reported, in mCRPC treatment monitoring.⁶⁰

Treatment inconvenience

This factor is a mix of treatment qualities, including treatment invasiveness, frequency, and duration.⁵⁵ People with mCRPC consistently rank treatment effectiveness and delay in time to symptoms as the most important treatment qualities.⁶¹

Selecting the optimal treatments and treatment sequence for a person with mCRPC, in the absence of validated predictive biomarkers, is an unmet need.^2-9 Sequential use of androgen-receptor signaling inhibitors (ARSI) for mCRPC is limited by cross-resistance between AR-targeted drugs, which further complicates treatment selection and sequencing.⁶²

For people with mCRPC in some lower-income countries, such as the Middle East or Africa, limited access to genetic testing and economic constraints are major unmet needs⁶³

Watch: Unmet needs in mCRPC

ESMO and NCCN guideline recommendations for mCRPC

Review clinical practice guideline recommendations for the “large armamentarium” of mCRPC treatments in less than 2 minutes, with Professor Merseburger. View transcript.

Table 1 summarizes European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guideline recommendations for mCRPC.

Table 1. ESMO and NCCN guideline recommendations for metastatic castration-resistant prostate cancer (Adapted^2-5,60,61). 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.

What guideline recommendations are challenging to apply in clinical practice?

Professor Fizazi identifies key factors that influence the implementation of mCRPC guideline recommendations in practice. View transcript.

Do treatment patterns for mCRPC follow guideline recommendations?

One real-world study evaluated country-specific clinical practice guidelines (CPG) for advanced prostate cancer and assessed treatment patterns for people with mCRPC in France, Germany, Italy, Spain, the UK, and Japan.⁶⁷

• 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 as backbone treatment^2-9,67
• The most common first- to second-line treatment sequence for mCRPC in the analyzed countries was ARSI, then chemotherapy⁶⁷

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 reimbursed.⁶⁷

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 mCRPC.^21,68

Factors that obstruct clinician adherence to oncology guidelines

No published study has investigated the 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 adherence.⁶⁹ Clinician adherence to oncology CPGs is obstructed by:⁶⁹

Concerns about CPG content and currency

Some CPGs are not consistently applicable to specific oncology settings, are unclear, and are 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 judgment. Clinical equipoise or clinical habits that diverge from CPG recommendations are potential barriers to CPG adherence.

Organizational concerns

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

Uptake of guideline recommendations

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 replacement.^2-9,67 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 CPGs.^2-9,67

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

Is precision oncology benefiting the mCRPC treatment landscape?

Professor Neeraj Agarwal (Huntsman Cancer Institute, University of Utah, USA) charts the progress of precision medicine in mCRPC to date, noting “the story doesn’t stop here.” View transcript.

Precision medicine in mCRPC

Genomic alterations tend to be heterogeneous in mCRPC and show specific effects in mCRPC progression and resistance to treatments.^18,70 Through an understanding of how specific genes or pathways are altered in an individual with mCRPC (Figure 5), precision medicine could advise on specific diagnostic tests and treatments for patients or patient subgroups.^18,70

Figure 5. Precision medicine in metastatic castration-resistant prostate cancer.⁷⁰ Reproduced from Ku et al.⁷⁰ with permission from Springer Nature. A, androgen; AR, androgen receptor; ARm, mutant AR; ARV, AR splice-variant; CDK, cyclin-dependent kinase; mCRPC, metastatic castration-resistant prostate cancer; PARPi, poly adenosine diphosphate-ribose polymerase inhibitor.

Altered androgen-receptor signaling in mCRPC

Genomic alterations that develop in 50–70% of people with mCRPC involve androgen receptor gene (AR) amplification, AR activating mutations (L702H, W742C, F877L, T878A), and AR structural changes, (deletion, duplication, inversion, translocation). These alterations reactivate AR signaling (Figure 6).^70,71

Figure 6. Altered androgen-receptor signaling in metastatic castration-resistant prostate cancer.⁷⁰ Reproduced from Ku et al.⁷⁰ with permission from Springer Nature. A, androgen; ABI, abiraterone; AR, androgen receptor; ARm, mutant AR; ENZA, enzalutamide; mut, mutation.

Clinical implications of altered androgen-receptor signaling in mCRPC

Alterations in AR gene signaling can lead to resistance to first-line AR-based treatments for mCRPC.⁷⁰ For example, sequential treatment with the androgen-synthesis inhibitor abiraterone followed by the androgen-receptor signaling inhibitor (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-resistance^72-74
• In the phase4 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 monotherapy⁷⁵
• In the ALLIANCE trial, combining abiraterone and enzalutamide revealed no differences in overall survival (OS) compared with enzalutamide alone⁷⁶

These data suggest that AR-based resistance mechanisms overlap in mCRPC, such that cross-treatment resistance remains unchanged following treatment with an ARSI.^18,70 As just one potential solution to persistent AR-driven disease, high-dose testosterone or “bipolar androgen therapy” (BAT) could restore responses to enzalutamide.⁷⁷ Other treatment solutions are under investigation.^18,70

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).^78,79 HSD3B1 could aid in stratifying patients for treatment intensification by biomarking individuals resistant to ADT.^18,70

Identification of biomarkers associated with the ARSI response could guide treatment selection in mCRPC.⁸⁰ In people with mCRPC receiving abiraterone, point mutations involving SPOP were associated with improved OS compared with those with wild-type SPOP.⁸⁰

Changes in the PTEN-PI3K-AKT pathway in mCRPC

Figure 7 shows dysregulated PI3K-AKT signaling in mCRPC. The tumor suppressor PTEN is deleted in ~50% of mCRPC tumors.⁸¹ Alterations in PIK3CA, PIK3CB, PIK3R1, and AKT1 are less commonly observed.^18,70

Figure 7. Dysfunctional PI3K-AKT signaling in metastatic castration-resistant prostate cancer.⁷⁰ Reproduced from Ku et al.⁷⁰ with permission from Springer Nature. Note: abiraterone acetate is converted in vivo to abiraterone, an androgen-synthesis inhibitor.^82,83 A, androgen; ABI, abiraterone; AKT, protein kinase B; AKTI, AKT inhibitor; AR, androgen receptor; 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 mCRPC.^18,70

PTEN deletion is linked to resistance to ARSI treatments.⁸⁴ For example, in people with mCRPC receiving abiraterone after docetaxel, in whom 40% had no PTEN tumor expression, an association was found between PTEN deletion and shorter OS (14 months compared with 21 months), and time using abiraterone.⁸⁴

The phase 3 IPATential150 trial investigated 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 population.⁸⁵ In the 521 (47%) patients with tumors 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).⁸⁶

Targeting other pathways, such as PI3K (Figure 7), has not proven successful, though early phase data on capivasertib are encouraging, and phase 3 trials are underway.^87,88

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).^70,89

Figure 8. DNA repair pathway in metastatic castration-resistant prostate cancer.⁷⁰ Reproduced from Ku et al.⁷⁰ with permission from Springer Nature. 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 people with mCRPC.^2-9,67

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.”⁹⁰ The phase 3 PROFOUND trial investigated the PARP inhibitor (PARPi) olaparib in people 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).⁴⁵ 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 genes.⁴⁵

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 group.⁴⁵

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 indicated.^19,23

Data on which genes to test for mCRPC, and which alterations respond best to PARPi or platinum chemotherapy, are needed^18,70

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).⁹¹

CDK12 inactivation (Figure 8) could define a specific class of mCRPC, which may benefit from immune checkpoint immunotherapy.⁹²

mCRPC with or without gene 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 patients.^81,93

RB1 loss is observed in approximately 10% of people with mCRPC and is associated with poor prognoses.⁹⁴ Alterations in CDK have been documented in 3–7% of people with mCRPC.⁹⁵

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 that can grow cancer cells (Figure 9).⁷⁰

Figure 9. Dysfunctional cell cycle in metastatic castration-resistant prostate cancer.⁷⁰ Reproduced from Ku et al.⁷⁰ with permission from Springer Nature. 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 death.⁹⁶ Small molecule kinase inhibitors are under investigation for prostate cancer, targeting key proteins recruited in the four phases of the cell cycle – G1 (gap), S (synthesis), and G2 (gap):

• G1: palbociclib⁹⁷
• S: berzosertib (M-6620)⁹⁸
• G2: adavosertib^99,100

In a completed trial of alisertib in people with metastatic prostate cancer and at least one small cell neuroendocrine morphology, or ≥50% neuroendocrine marker expression, or new liver metastases without PSA progression, or elevated serum neuroendocrine markers, 6-month rPFS was 13.4% and median OS was 9.5 months (7.3–13). Four exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity.¹⁰¹

Future innovations in precision medicine for mCRPC

Whole-genome sequencing

Targeted and whole-exome sequencing studies have identified recurrent alterations in mCRPC involving coding genes.^18,70 Whole-genome sequencing (WGS) could describe the full genomic landscape of structural variations in mCRPC.^18,70 WGS shows that 70–87% of mCRPC tumors amplify an upstream enhancer of the AR gene, resulting in AR overexpression, and could contribute to ARSI treatment resistance.^16,102,103

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 tumor sampling in mCRPC.¹⁰⁴

Meeting unmet needs using precision oncology for metastatic prostate cancer

Table 2 describes approaches, techniques, and tools to help address unmet needs using precision oncology in metastatic prostate cancer.^18,70

Table 2. Strategies to address unmet needs using precision oncology for metastatic prostate cancer.^18,70 CT, computerized tomography; PSMA-PET, prostate-specific membrane antigen positron-emission tomography.

To help meet unmet treatment needs for metastatic castration-resistant prostate cancer (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 (Institut Gustave Roussy, Villejuif, France) describes key target pathways that influence choice of therapy for mCRPC. View transcript.

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).^21,68

Table 3. Candidate first-line treatments for mCRPC.²¹ ADT, androgen deprivation therapy; ARSI, androgen-receptor signaling inhibitor; 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.

Investigational combination treatments for mCRPC

MAGNITUDE

In the ongoing 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).¹⁰⁵

The final 3-year update and analysis favored niraparib with abiraterone acetate plus prednisone (AAP) versus placebo with abiraterone acetate plus prednisone for:¹⁰⁶

• Overall survival (OS; multivariate analysis) (HR, 0.66; 95% CI, 0.46–0.95; P=0.02)
• Time to symptomatic progression (HR, 0.56; 95% CI, 0.37–0.85; P=0.01)
• Time to cytotoxic chemotherapy (HR, 0.60; 95% CI, 0.39–0.92; P=0.02)
• Time to worst pain progression (HR, 0.81; 95% CI, 0.52–1.25)
• Time to pain interference progression (HR, 0.77; 95% CI, 0.48–1.23)

MAGNITUDE second interim analysis supported niraparib + AAP for mCRPC and HRR alterations, especially for BRCA1/2.¹⁰⁷

PROpel

In the phase 3 PROpel trial, the combination of abiraterone–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.¹⁰⁸

At the prespecified final analysis, OS in the abiraterone–olaparib group was not significantly different from that in the abiraterone–placebo group (maturity 47.9%; HR, 0.81; 95% CI, 0.67–1.00; P=0.0544). No long-term safety issues were identified.¹⁰⁹

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).¹¹⁰ The primary endpoint was rPFS.

TALAPRO-2, part 1

In part 1 of TALAPRO-2, treatment-emergent adverse events (TEAEs) 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 exposure.¹¹⁰

Based on these safety data, talazoparib 0.5 mg QD plus enzalutamide 160 mg QD is the starting dose for the ongoing TALAPRO-2, part 2. The primary endpoint was rPFS.⁴⁶

TALAPRO-2, part 2

In patients with any HRR gene alteration, rPFS was significantly improved in the talazoparib–enzalutamide cohort, compared with placebo–enzalutamide cohort (HR, 0.45; 95% CI, 0.33–0.61; P<0.001; median not reached at the time of analysis versus 13.8 months). A consistent treatment effect for rPFS was observed across prespecified clinical subgroups. In a post hoc analysis, patients with BRCA1/BRCA2 alterations treated with talazoparib–enzalutamide had an 80% lower risk of radiographic progression or death (HR, 0.20; 95% CI, 0.11–0.36; P<0.0001).¹¹¹

OS data are immature. Most patients are alive: at data cut-off, 43 (22%) patients in the talazoparib group and 53 (27%) in the placebo group had died.¹¹¹

Talazoparib–enzalutamide improved secondary endpoints objective response rate (ORR), prolonged time to prostate-specific antigen (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 subgroups.¹¹²

The most common TEAEs for talazoparib were anemia, neutropenia, and fatigue; the most common grade 3–4 TEAE was anemia, which improved after dose reduction; 33 (8%) of 398 patients discontinued talazoparib because of anemia.^46,111

Longer rPFS was associated with higher average talazoparib concentrations, which supports using 0.5 mg QD (with enzalutamide) for mCRPC.¹¹³

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 germline HRR mutations in placebo–enzalutamide, which suggests a poor prognosis subgroup that could be prioritized for talazoparib–enzalutamide treatment.¹¹⁴

TALAPRO-3

TALAPRO-3 is an ongoing phase 3, randomized study of enzalutamide plus talazoparib, versus placebo plus enzalutamide, in patients with DDR/HRR gene-altered metastatic castration-sensitive prostate cancer (mCSPC).⁴⁹ The primary endpoint is rPFS.⁴⁹ TALAPRO-3 is expected for completion in 2027.¹¹⁵

RAMP; CASPAR

In the completed phase 1b RAMP study, rucaparib plus enzalutamide induced a decline in PSA in three-fourths of participants (six of eight patients), and a PSA response in half (four of eight patients).¹¹⁶

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 mCRPC.¹¹⁷ Co-primary endpoints are rPFS and OS.¹¹⁷

Download this infographic linking genomic and transcriptomic alterations in mCRPC

¹⁷⁷Lu-PSMA-617

VISION

Prostate-specific membrane antigen (PSMA) is expressed in mCRPC.¹¹⁸ In people with mCRPC, metastatic lesions are PSMA-positive,¹¹⁹ and expression is correlated with reduced survival.^{120 177}Lu-PSMA-617, a radioligand therapy, sends beta-particle radiation to PSMA-expressing cells.¹²¹

The completed 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)-labeled 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).¹²²

¹⁷⁷Lu-PSMA-617 plus SoC delayed time to worsening health-related quality of life (HRQoL), pain, and time to skeletal events compared with SoC.¹²³ However, in a post hoc analysis of VISION, rPFS correlated strongly with OS, but not with time to symptomatic skeletal events or worsening HRQoL.¹²⁴

TheraP

A direct comparison between ¹⁷⁷Lu-PSMA-617 and cabazitaxel was conducted in TheraP.¹²⁵ In this completed 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%).¹²⁶

After a median follow-up of 35.7 months, 77 (78%) participants died in the ¹⁷⁷Lu-PSMA-617 group and 70 (69%) died in the cabazitaxel group. OS was similar for ¹⁷⁷Lu-PSMA-617 and cabazitaxel (restricted mean survival time, 19.1 months [95% CI, 16.9–21.4] vs 19.6 months [17.4–21.8]; difference –0.5 months [95% CI, –3.7 to 2.7]; P=0.77).¹²⁷

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 chemotherapy¹²⁸

Ongoing combination trials for mCRPC

• COMRADE (Radium-223 + olaparib vs radium-223) for study completion in 2024¹²⁹
• DORA (Radium-223 + docetaxel vs docetaxel) for study completion in 2025¹³⁰
• AlphaBet (¹⁷⁷Lu-PSMA-617 + radium-223) aims for study completion in 2026¹³¹
• CYCLONE-2 (abemaciclib + abiraterone + prednisone vs placebo + abiraterone + prednisone) for study completion in 2026¹³²
• PEACE-3 (radium-223 + enzalutamide vs enzalutamide) for study completion in 2028¹³³

Investigational treatments for mCRPC

Current clinical practice guidelines for metastatic castration-resistant prostate cancer (mCRPC) advise first-line androgen-receptor signaling inhibitor (ARSI) followed by chemotherapy as the preferred treatment sequence.^2-9 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 uncertainty.^134,135

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 trials.¹³⁴

A speculative mCRPC treatment algorithm (sequencing and intensification), encompassing four possible scenarios, has been proposed (Figure 10).¹³⁵

Figure 10. Proposed treatment algorithm (sequencing and intensification) for metastatic castration-resistant prostate cancer. Image licensed under CC-BY-NC-ND 4.0 from Turco et al.¹³⁵ *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-signaling 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 androgen deprivation therapy monotherapy, docetaxel or ARSIs are an option, and abiraterone plus poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) can be considered if a DNA damage repair (DDR) gene mutation is detected. Receipt of abiraterone plus PARPi as first-line treatment should receive second-line docetaxel, while cabazitaxel, radium-223, and ¹⁷⁷lutetium-PSMA-617 should be in subsequent lines.¹³⁵

Scenario 2

ARSI is a first-line option for people with mCRPC who have progressed after docetaxel in the metastatic hormone-sensitive prostate cancer setting. Cabazitaxel is a consideration for patients with poor prognostic factors. In case of DDR mutations in mCRPC, abiraterone plus PARPi as a first-line option can be considered.¹³⁵

Scenario 3

For patients treated with apalutamide in early mCRPC, sequential use of ARSIs can be considered.¹³⁵

Scenario 4

Cabazitaxel is an option for 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-617.¹³⁵

In the PEACE-1¹³⁶ and ARASENS¹³⁷ 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 metastatic prostate cancer.¹³⁵

Although broad guideline recommendations for treatment sequencing are possible in the mCRPC setting, these must be tailored to the individual^2-9