Study of AZD4956 as Monotherapy and in Combination With Anti-Cancer Agents in Participants With Advanced/Metastatic Homologous Recombination Deficient Solid Tumours

Objective response (OR)

OR is defined as if a participant achieves a best overall response (BOR) of confirmed complete response (CR) or partial response (PR), as assessed by the investigator, according to response evaluation criteria in solid tumours (RECIST) v1.1 criterion.

Time frame: Up to 3.5 years

Duration of response (DoR)

DoR is defined as the time from the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by prostate cancer working group 3 (PCWG3), until the date of documented disease progression or death in the absence of disease progression.

Time frame: Up to 3.5 years

Best Overall Response (BOR)

To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer agent(s).

Time frame: Up to 3.5 years

Time to response (TTR)

TTR is defined as the time from the date of first dose of study intervention until the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, which is subsequently confirmed.

Time frame: Up to 3.5 years

Disease control (DC)

DC is defined as if a participant has achieved a best OR of confirmed CR or PR or SD as BOR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3.

Time frame: Up to 3.5 years

Clinical benefit rate (CBR)

CBR is defined as the percentage of advanced cancer participants who achieve CR, PR, or at least 16 weeks/24 weeks of stable disease, assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, as a result of therapy.

Time frame: Up to 3.5 years

Part A: Progression free survival (PFS)

PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression.

Time frame: Up to 3.5 years

Percentage change from baseline in tumour size

The best percentage change from baseline in target lesion (TL) tumour size is the largest decrease (or smallest increase) from baseline for a participant, using RECIST v1.1 assessments.

Time frame: Up to 3.5 years

Number of participants with cancer antigen 125 (CA125) response (for ovarian cancer participants)

CA125 response is defined as if at least a 50% reduction in CA125 levels from a pre-treatment sample.

Time frame: From baseline up to 3.5 years

Radiological progression free survival (rPFS) (for prostate cancer participants)

PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression.

Time frame: Up to 3.5 years

Change from baseline in prostate specific antigen 50 (PSA50) response rate (for prostate cancer participants)

PSA50 response is defined as if a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved.

Time frame: From baseline up to 3.5 years

Change from baseline in PSA90 response rate (for prostate cancer participants)

PSA90 response is defined as if a ≥ 90% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved.

Time frame: From baseline up to 3.5 years

Change from baseline in PSA undetectable rate

Undetectable PSA is defined as a measurement of \< 0.2 ng/mL.

Time frame: At 3, 6 and 9 months

Time to PSA50/90 response (for prostate cancer participants)

Time to PSA50/90 response is defined as the time from the date of first dose of study intervention until the date of first documented PSA response (≥ 50%/90% decrease in PSA from baseline) that is confirmed by a second consecutive PSA assessment at least 3 weeks later.

Time frame: Up to 3.5 years

Time to PSA progression (for prostate cancer participants)

Time to PSA progression is defined as the time from date of first dose of study intervention until the date of first documented PSA progression or the last PSA result in the absence of progression.

Time frame: Up to 3.5 years

PSA PFS at 6 months (PSA-6)

PSA progression is defined as an increase in PSA of ≥ 25% from the nadir and an absolute increase of at least 2 ng/mL above nadir beyond 12 weeks. To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer. agent(s)

Time frame: At 6 months

Area under the concentration-time curve (AUC)

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 59 days after first dose

Maximum concentration (Cmax)

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 59 days after first dose

Time to maximum concentration (Tmax)

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 59 days after first dose

Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe(t1-t2))

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 16 days after first dose

Renal clearance (CLR)

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 16 days after first dose

Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae(t1-t2))

To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From date of first dose of study intervention up to 16 days after first dose

Change in amount of KRAB-associated protein-1 phosphorylated on serine 824 [pKAP1 (Ser824)] biomarker in tumour cells at baseline and during treatment

To evaluate PD of AZD4956 in tumour cells when given orally as monotherapy and in combination with anti-cancer agent(s).

Time frame: From Baseline up to 3.5 years